Atrofia wieloukładowa – Etiologia i przyczyny

Atrofia wieloukładowa
Etiologia i przyczyny

Atrofia wieloukładowa (MSA) to postępujące, śmiertelne schorzenie neurodegeneracyjne charakteryzujące się parkinsonizmem, ataksją móżdżkową i dysfunkcją autonomiczną, z medianą przeżycia 6-10 lat od diagnozy. Patognomonicznym markerem jest akumulacja hiperfosforylowanej alfa-synukleiny w oligodendrocytach, tworząca inkluzje cytoplazmatyczne (ciała Pappa-Lantosa), co odróżnia MSA od choroby Parkinsona, gdzie agregaty białka lokalizują się głównie w neuronach. Hipoteza prionowa sugeruje zakaźny charakter alfa-synukleiny w MSA, potwierdzony eksperymentalnie na modelach mysich, co wskazuje na odrębność patomechanizmu względem innych synukleinopatii. Patologia obejmuje głównie istotę białą, z wtórnym uszkodzeniem neuronów, a dysfunkcja mitochondrialna, neuroinflammacja, zaburzenia autofagii i proteasomów oraz dysregulacja metabolizmu żelaza są uznawane za kluczowe mechanizmy patogenetyczne.

Wprowadzenie do atrofii wieloukładowej

Atrofia wieloukładowa (Multiple System Atrophy, MSA) to rzadkie, postępujące neurodegeneracyjne schorzenie, które charakteryzuje się objawami parkinsonizmu, ataksji móżdżkowej, dysfunkcji autonomicznej oraz innymi objawami ruchowymi i pozaruchowymi. Choroba prowadzi do degeneracji wielu obszarów mózgu, w tym prążkowia, istoty czarnej, móżdżku i pnia mózgu. MSA jest zawsze śmiertelna, a średni czas przeżycia wynosi około 6-10 lat od momentu diagnozy. Mimo intensywnych badań, etiologia tej choroby pozostaje w dużej mierze nieznana.¹²

Patofizjologia akumulacji alfa-synukleiny

Głównym markerem neuropatologicznym atrofii wieloukładowej jest nieprawidłowa akumulacja białka alfa-synukleiny w komórkach glejowych i neuronach. W przeciwieństwie do choroby Parkinsona, gdzie alfa-synukleina gromadzi się głównie w neuronach, w MSA białko to akumuluje się przede wszystkim w oligodendrogleju, tworząc charakterystyczne inkluzje cytoplazmatyczne zwane ciałami Pappa-Lantosa.³⁴

Mikroskopowe badanie tkanki mózgowej pacjentów z MSA wykazuje wyraźną obecność cytoplazmatycznych inkluzji glejowych (GCIs), które są znakiem rozpoznawczym choroby. Te inkluzje zawierają nieprawidłowo sfałdowane, hiperfosforylowane włókienkowe alfa-synukleiny, które prowadzą do dysfunkcji komórkowej i postępującej utraty funkcji komórek nerwowych.⁵⁶

Gęstość inkluzji cytoplazmatycznych glejowych zawierających alfa-synukleinę jest istotnie skorelowana z nasileniem neurodegeneracji i czasem trwania choroby. Badania sugerują, że różnorodne formy i struktury alfa-synukleiny mogą wyjaśniać, dlaczego białko to gromadzi się w komórkach glejowych w MSA, a w komórkach nerwowych w chorobie Parkinsona.⁷⁸

Teoria prionowa

Jedna z nowszych teorii wyjaśniających mechanizm rozprzestrzeniania się patologii w MSA opiera się na hipotezie prionowej. W 2015 roku badanie opublikowane w Proceedings of the National Academy of Sciences zasugerowało, że MSA może być chorobą prionową, z alfa-synukleiną jako cząsteczką zakaźną.⁹

Doktor Stanley Prusiner przedstawił wyniki eksperymentów, w których próbki alfa-synukleiny pobrane z mózgów 14 pacjentów z MSA zostały przeniesione do homozygotycznych myszy. Po okresie inkubacji trwającym 120 dni, u myszy rozwinęła się neurodegeneracja, której towarzyszyło odkładanie się alfa-synukleiny w ciałach komórkowych i aksonach. Myszy kontrolne zakażone alfa-synukleiną z mózgów pacjentów z chorobą Parkinsona nie rozwinęły neurodegeneracji. Chociaż teoria ta pozostaje kontrowersyjna, wyniki są przekonujące i sugerują, że pomimo podobieństw klinicznych i patologicznych, MSA i choroba Parkinsona są odrębnymi punktami na spektrum neurodegeneracji.¹⁰

Rola oligodendrogleju

Szczególny wzorzec neuropatologiczny choroby, charakteryzujący się akumulacją alfa-synukleiny w oligodendrocytach, skłonił wielu badaczy do skupienia się na tym aspekcie i postawienia hipotezy, że MSA jest pierwotnie oligodendrogliopatią, z wtórnym zajęciem neuronów.¹¹

Badacze początkowo zakładali, że uszkodzenie istoty szarej powoduje MSA. Jednak odkrycie oligodendroglialnych cytoplazmatycznych inkluzji (GCIs) wskazało, że uszkodzenie dotyczy przede wszystkim istoty białej. Przewlekłe zmiany w komórkach glejowych mogą zaburzać funkcję troficzną między oligodendrocytami a aksonami i powodować wtórne uszkodzenie neuronów.¹²

Zaproponowano hipotezę, że inkluzje alfa-synukleiny znalezione w oligodendrocytach są wynikiem przycinania i pochłaniania chorych segmentów aksonalnych zawierających zagregowaną alfa-synukleinę, czyli neurytów Lewy’ego.¹³

Czynniki genetyczne w MSA

Chociaż MSA jest powszechnie uważana za chorobę sporadyczną, ostatnie badania wskazują na potencjalny udział czynników genetycznych w jej rozwoju.¹⁴¹⁵

Mutacje i polimorfizmy genowe

Badania genetyczne wykazały kilka potencjalnych genów kandydatów i loci związanych z ryzykiem rozwoju MSA:

Gen SNCA (kodujący alfa-synukleinę) – polimorfizmy pojedynczych nukleotydów (SNPs) w loci SNCA zostały zidentyfikowane u pacjentów z MSA. Warianty genu SNCA są związane ze zwiększonym ryzykiem rozwoju MSA, szczególnie u osób rasy kaukaskiej.¹⁶¹⁷
Gen COQ2 – mutacje w tym genie, kodującym enzym zaangażowany w biosyntezę koenzymu Q10, zostały opisane w wieloosobowych rodzinach z MSA, a niektóre warianty były związane ze zwiększonym ryzykiem sporadycznej MSA. Jednak wyniki te nie zostały potwierdzone we wszystkich badanych kohortach pacjentów.¹⁸¹⁹
Gen GBA – wariant w genie GBA, kodującym enzym glukocerebrozydazę, okazał się nieco częstszy u osób z MSA niż w pozostałej części populacji.²⁰²¹

Dodatkowo badania wykazały potencjalny związek polimorfizmów genów zapalnych, takich jak IL-1α, IL-1β, IL-8, ICAM-1, α-1-antychymotrypsyna, geny czynnika martwicy nowotworów, a także SLC1A4, SQSTM1 i EIF4EBPI z predyspozycją do MSA.²²

Dziedziczenie MSA

Istnieją doniesienia o przypadkach rodzinnych MSA, chociaż są one bardzo rzadkie. Jedna analiza wykazała korelację między delecją genów w określonym regionie genetycznym a rozwojem MSA w grupie japońskich pacjentów. Badanie przeprowadzone w populacji amerykańskiej nie potwierdziło jednak podobnych wyników.²³

W niektórych przypadkach MSA typu móżdżkowego (MSA-C) zaobserwowano dziedziczenie autosomalne recesywne. Przypadki rodzinne MSA-C zostały również powiązane z mutacją w genie ataksji rdzeniowo-móżdżkowej typu 3 (SCA3).²⁴²⁵

Mimo tych odkryć, większość przypadków MSA nie wydaje się być bezpośrednio dziedziczona i występuje sporadycznie. Niektórzy naukowcy sugerują, że polimorfizmy genetyczne mogą raczej zwiększać podatność na rozwój choroby niż być jej bezpośrednią przyczyną.²⁶

Czynniki środowiskowe

Chociaż dotychczas nie zidentyfikowano definitywnych czynników środowiskowych powodujących MSA, badania wskazują na potencjalny związek niektórych ekspozycji środowiskowych z rozwojem choroby.²⁷

Ekspozycja na substancje toksyczne

Kilka badań wykazało potencjalny związek między ekspozycją na toksyny środowiskowe a zwiększonym ryzykiem MSA:

Narażenie na metale ciężkie – pył i opary metalowe²⁸
Ekspozycja na monomery plastikowe i dodatki²⁹
Kontakt z rozpuszczalnikami organicznymi³⁰
Narażenie na pestycydy – chociaż związek ten został zasugerowany, nie został statystycznie potwierdzony³¹

Jedno małe badanie wykazało, że osoby dotknięte MSA miały wyższe wskaźniki narażenia na toksyny, takie jak pył metali, pestycydy, rozpuszczalniki organiczne i tworzywa sztuczne, w porównaniu z grupą kontrolną.³²

Narażenie na te czynniki środowiskowe może zmieniać krajobraz epigenetyczny, potencjalnie wpływając na ekspresję genów związanych z ryzykiem MSA. Jednak mechanizmy epigenetyki środowiskowej nie zostały jeszcze dokładnie zbadane w kontekście MSA.³³

Mechanizmy dysfunkcji komórkowej w MSA

Oprócz akumulacji alfa-synukleiny, badacze zidentyfikowali kilka innych potencjalnych mechanizmów komórkowych przyczyniających się do patogenezy MSA.³⁴

Dysfunkcja mitochondrialna

Ostatnie badania wskazują na potencjalną rolę dysfunkcji mitochondrialnej w patogenezie MSA. Interesujący jest fakt, że jeden z pierwszych modeli zwierzęcych choroby (obecnie już niestosowany) został uzyskany poprzez podawanie zwierzętom inhibitora dehydrogenazy bursztynianowej (kompleks II łańcucha oddechowego) – kwasu 3-nitropropionowego (kwas 3-NP), ze względu na jego zdolność do wywoływania uszkodzeń prążkowia.³⁵

Związek z dysfunkcją mitochondrialną wzmacniają również odkrycia dotyczące mutacji w genie COQ2, który koduje enzym uczestniczący w produkcji koenzymu Q10, ważnego dla wytwarzania energii przez komórki mózgowe.³⁶

Zaburzenia układu odpornościowego i stan zapalny

Neuroinflammacja została zaproponowana jako potencjalny mechanizm w patogenezie MSA. Wykazano zwiększony poziom stanu zapalnego w mózgach osób z MSA, chociaż nie jest jasne, czy jest to przyczyna choroby, czy efekt uboczny procesu chorobowego.³⁷

Aktywacja mikrogleju, uwalnianie cytokin i chemokin oraz stan zapalny mogą przyspieszać agregację alfa-synukleiny i apoptozę oligodendrogleju.³⁸

Sugerowano również mechanizmy autoimmunologiczne jako potencjalne przyczyny MSA, ale dowody na ich poparcie są słabe.³⁹

Zaburzenia degradacji białek

Dysfunkcja autofagii i proteasomów może przyczyniać się do akumulacji alfa-synukleiny w MSA. Upośledzona degradacja białek może prowadzić do nagromadzenia nieprawidłowo sfałdowanych protein, które ostatecznie tworzą toksyczne agregaty.⁴⁰

Dysregulacja metabolizmu żelaza

Odkrycie zwiększonego poziomu żelaza w określonych regionach mózgu pacjentów z MSA doprowadziło do hipotezy, że dysregulacja metabolizmu żelaza może odgrywać rolę w patogenezie choroby.⁴¹

Koncepcja wieloczynnikowej etiologii MSA

Biorąc pod uwagę złożoność patologii MSA, wielu badaczy sugeruje, że choroba ta może być wynikiem współdziałania wielu czynników, a nie pojedynczej przyczyny.⁴²⁴³

Model „wielu uderzeń”

Intrygująca jest hipoteza, że MSA jest chorobą wieloczynnikową spowodowaną połączonym efektem wielu „uderzeń” (ang. multiple hits). W tym modelu, szereg różnych czynników ryzyka – genetycznych, środowiskowych i innych – współdziała, prowadząc do rozwoju choroby.⁴⁴

Wciąż nie jest jasne, która z proponowanych przyczyn (np. akumulacja białka, dysfunkcja mitochondrialna, stan zapalny) stanowi pierwotny epizod wyzwalający całą kaskadę patogenną. Sekwencja czasowa zdarzeń patogennych pozostaje niejasna.⁴⁵

Rola czynników demograficznych

MSA najczęściej diagnozuje się u mężczyzn po 60. roku życia. Płeć i wiek mogą być czynnikami ryzyka rozwoju choroby.⁴⁶⁴⁷

Częstość występowania MSA wynosi około 3 na 100 000 osób, ale częstość i podtyp MSA różnią się znacznie w zależności od położenia geograficznego i pochodzenia etnicznego.⁴⁸

Badania nad poznaniem etiologii MSA i perspektywy terapeutyczne

Znaczenie zrozumienia mechanizmów molekularnych choroby ma nie tylko cele czysto spekulatywne, ale znajduje również praktyczne zastosowanie w identyfikacji nowych biomarkerów i podejść terapeutycznych.⁴⁹

Bieżące badania genetyczne

Trwające badania genetyczne i translacyjne otwierają nowe drzwi w zrozumieniu patogenezy MSA. Wielonarodowe i wieloośrodkowe badania z danymi z długoterminowej obserwacji będą pomocne w identyfikacji rzadkich wariantów genów o niewielkich rozmiarach efektu i określeniu heterogeniczności między różnymi grupami wiekowymi, płciowymi i etnicznymi.⁵⁰

Badacze mają nadzieję, że skojarzenia genetyczne mogą dać dalsze wskazówki dotyczące patogenezy MSA, a także cele dla interwencji terapeutycznych.⁵¹

Badania funkcjonalne i nowe kierunki terapeutyczne

Badania funkcjonalne na modelach zwierzęcych i ludzkich różnych zidentyfikowanych wariantów/mutacji genetycznych mogą zidentyfikować nowe wskazówki patofizjologiczne, które mogą prowadzić do opracowania modyfikujących przebieg choroby celów terapeutycznych.⁵²

Trwają badania nad potencjalnymi terapiami modyfikującymi przebieg choroby, od autofagii, przez aktywną immunizację, szczepienia, po komórki macierzyste. Badacze mają nadzieję dowiedzieć się, dlaczego dochodzi do nagromadzenia alfa-synukleiny w MSA i chorobie Parkinsona oraz jak temu zapobiec.⁵³⁵⁴

Leki zmniejszające nieprawidłowe nagromadzenie alfa-synukleiny mogą być obiecującymi metodami leczenia MSA. Badania nad tymi potencjalnymi terapiami są obecnie w toku.⁵⁵

Podsumowanie obecnego stanu wiedzy

Pomimo intensywnych badań, dokładna etiologia atrofii wieloukładowej pozostaje w dużej mierze nieznana. Obecny stan wiedzy wskazuje na złożoną interakcję między czynnikami genetycznymi, środowiskowymi i komórkowymi w patogenezie choroby.⁵⁶⁵⁷

Charakterystyczne dla MSA jest gromadzenie się alfa-synukleiny w komórkach glejowych, zwłaszcza w oligodendrocytach, co odróżnia ją od innych synukleinopatii, takich jak choroba Parkinsona, gdzie białko to gromadzi się głównie w neuronach.⁵⁸

Badania genetyczne zidentyfikowały kilka potencjalnych genów kandydatów związanych z ryzykiem MSA, w tym SNCA, COQ2 i GBA, chociaż żaden z nich nie wydaje się być głównym genem przyczynowym. Podobnie, badania środowiskowe sugerują potencjalne związki z ekspozycją na metale, pestycydy i rozpuszczalniki organiczne, ale dowody nie są ostateczne.⁵⁹

Trwające badania nad mechanizmami komórkowymi, takimi jak dysfunkcja mitochondrialna, neuroinflammacja i zaburzenia degradacji białek, a także badania nad potencjalnymi właściwościami prionopodobnymi alfa-synukleiny, oferują nowe kierunki zrozumienia patogenezy MSA i opracowania skutecznych terapii.⁶⁰

Zrozumienie przyczyn MSA pozostaje kluczowym wyzwaniem badawczym w neurologii, a poznanie mechanizmów leżących u podstaw tej choroby ma fundamentalne znaczenie dla opracowania skutecznych terapii modyfikujących jej przebieg.⁶¹

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Materiały źródłowe

#1 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
Multiple System Atrophy (MSA) is a severe neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, dysautonomia and other motor and non-motor symptoms. […] Although several efforts have been dedicated to understanding the causative mechanisms of the disease, MSA pathogenesis remains widely unknown. […] Although the cause of MSA is still obscure, a relevant effort has been dedicated to understanding the pathogenic mechanisms. […] This review focuses on -syn accumulation, which is by far the most widely investigated mechanism, and mitochondrial dysfunction, whose analysis has provided relevant advances in recent years. […] Several hypotheses have been proposed to explain the aberrant localization of -syn in MSA. […] The hypothesis of an aberrant SNCA expression in MSA oligodendroglia is intriguing, but the conflicting available data do not allow one to draw definite conclusions about this issue.
#2 Multiple System Atrophy: Practice Essentials, Background, Etiology and Pathophysiology
https://emedicine.medscape.com/article/1154583-overview
Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. […] The cause of MSA remains unknown, and no current therapy can reverse or halt progression of the disease. […] The cause of MSA remains unclear, although a history of trauma has been suggested. Pesticide exposure as a causative factor in MSA has been suggested but has not been confirmed statistically. […] Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak. […] There is some evidence of genetic predispositions in Japanese cohorts. Autosomal recessive inheritance and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported.
#3 Multiple System Atrophy | National Institute of Neurological Disorders and Stroke
https://www.ninds.nih.gov/health-information/disorders/multiple-system-atrophy
Research findings indicate that abnormal alpha-synuclein accumulation in nerve cells and their supporting cells, including glia, leads to cellular dysfunction and progressive loss of nerve cell function (known as neurodegeneration). […] Studies suggest that the diverse forms and structures of alpha-synuclein might explain why the protein accumulates in glial cells in MSA and nerve cells in Parkinson’s disease. […] Ongoing research is currently focused on finding ways to prevent and treat alpha-synuclein from building up and spreading throughout the brain.
#4 Multiple system atrophy: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/multiple-system-atrophy/
In all cases, multiple system atrophy is characterized by clumps of abnormal alpha-synuclein protein that, for unknown reasons, build up in cells in many parts of the brain and spinal cord. Over time, these clumps (which are known as inclusions) damage cells in parts of the nervous system that control movement, balance and coordination, and autonomic functioning. The progressive loss of cells in these regions underlies the major features of multiple system atrophy.
#5 Multiple System Atrophy: Causes and Treatment | Doctor
https://patient.info/doctor/multiple-system-atrophy
Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder, caused by cell loss in areas of the brain and the spinal cord, leading to a variety of symptoms affecting especially the functions of the autonomic nervous system and the motor system. […] The aetiology is not fully understood. It is thought likely that a combination of genetic and environmental factors plays a part in the development of MSA though neither genetic nor environmental causes have yet been found. […] There seems to an accumulation of intracellular alpha-synuclein, particularly in oligodendrocytes which may cause MSA. […] MSA is characterised by widespread glial cytoplasmic inclusions (GCIs) which are the hallmark of the disease. More recently, misfolded, hyperphosphorylated fibrillar -synuclein has been identified as the main component of GCIs.
#6 Multiple system atrophy | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/multiple-system-atrophy?lang=us
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease and synucleinopathy characterized by varying degrees of cerebellar ataxia, autonomic dysfunction, parkinsonism, and corticospinal dysfunction. […] Like other synucleinopathies, MSA results from abnormalities of alpha-synuclein metabolism, resulting in intracellular deposition. […] Unlike Parkinson disease and Lewy body dementia (two other synucleinopathies), these intracellular deposits are found not only in neurons but also in oligodendroglia.
#7 Multiple System Atrophy: Causes and Treatment | Doctor
https://patient.info/doctor/multiple-system-atrophy
The density of GCI containing -synuclein correlates significantly with neuronal deterioration and disease duration. Another important protein, p25 has been found to stimulate -synuclein in vitro. It is thought that there may be both genetic and environmental processes that contribute to these pathological processes. […] Ongoing studies suggest that this excess alpha-synuclein is either a result of genetic overexpression in oligodendrocytes of affected patients or a result of increased uptake from the surrounding extracellular environment. Some patients with MSA have been shown to have COQ2 gene which codes for Coenzyme Q10, although this has only been shown in the cerebellar form of MSA.
#8 Multiple System Atrophy | National Institute of Neurological Disorders and Stroke
https://www.ninds.nih.gov/health-information/disorders/multiple-system-atrophy
Research findings indicate that abnormal alpha-synuclein accumulation in nerve cells and their supporting cells, including glia, leads to cellular dysfunction and progressive loss of nerve cell function (known as neurodegeneration). […] Studies suggest that the diverse forms and structures of alpha-synuclein might explain why the protein accumulates in glial cells in MSA and nerve cells in Parkinson’s disease. […] Ongoing research is currently focused on finding ways to prevent and treat alpha-synuclein from building up and spreading throughout the brain.
#9 Azthena logo with the word Azthena
https://www.news-medical.net/health/Causes-of-Multiple-System-Atrophy.aspx
The fundamental cause of multiple system atrophy (MSA) is a loss of oligodendroglial and neuronal cells in the brain and central nervous system. The loss of cells is gradual and progressive, leading to slowly worsening symptoms. […] However, what triggers the initial and ongoing loss of cells is unknown. […] Those results suggest that there may be a genetic vulnerability to MSA that can be activated by toxic environmental exposures. […] Further genetic studies have identified single nucleotide polymorphisms in a genetic location coding for alpha-synuclein. […] A study published in 2015 in Proceedings of the National Academy of Sciences took things a step further and designated MSA as a prion disease, with alpha-synuclein as the infectious particle. […] This would make MSA the first new prion disease discovered since CJD.
#10 Multiple System Atrophy-D Maybe Something AltogetherâDifferent
https://practicalneurology.com/articles/2018-mar-apr/multiple-system-atrophy-d-maybe-something-altogetherdifferent
The prion hypothesis, a theory that has been gaining support, was presented as the plenary lecture. Dr. Stanley Prusiner discussed experiments in which -synuclein samples from the brains of 14 patients who had MSA were transmitted to homozygous mice. After an incubation of 120 days, the mice developed neurodegeneration that was accompanied by deposition of -synuclein in cell bodies and axons. Control, sham-infected mice as well as those infected with -synuclein from the brains of patients who had PD did not develop neurodegeneration. Although controversial, these data are compelling and support the idea that despite clinical and pathologic similarities, MSA and PD are distinct points on a spectrum of neurodegeneration. […] As with most neurodegenerative diseases, we are at a fork in the road, with one path leading toward disease-modifying treatments and the other to symptomatic management. For the latter, currently in phase 2 trials, TD-9855 is being studied for the treatment of neurogenic orthostatic hypotension, as a daily-dose compound with vasogenic tone properties. For disease modification, studies of possible therapies run the gamut from autophagy, to active immunization, vaccination, and stem cells. […] Although it is likely that MSA and PD will always be intertwined, MSA is emerging as a distinct pathology.
#11 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
A new field of investigation derives from the recent description of a prion-like spreading pathology of -syn in MSA. […] Recent studies have pointed out the role of specific -syn strains in the pathogenesis of synucleinopathies. […] Impaired protein degradation may also be involved in -syn accumulation, as suggested by the description of a possible role of autophagic and proteasomal dysfunction in the disease. […] The finding of an increased iron level in specific brain regions of MSA patients has led to the hypothesis that iron metabolism dysregulation may play a role in the pathogenesis of the disease. […] Although several efforts have been dedicated to unravelling the causes of MSA, the precise pathogenic mechanisms underlying this disorder still have to be elucidated. […] The peculiar neuropathological pattern of the disease, characterized by -syn accumulation in oligodendrocytes, has led many investigators to focus on this particular aspect and to hypothesize that MSA primarily represents an oligodendrogliopathy, with a secondary neuronal involvement.
#12 Multiple System Atrophy: Practice Essentials, Background, Etiology and Pathophysiology
https://emedicine.medscape.com/article/1154583-overview
Single nucleotide polymorphisms (SNPs) at the SNCA locus coding for alpha-synuclein have been identified. G51D mutation in the SNCA locus has been described, but a connection between SCNA locus and MSA disease could not be confirmed. […] Researchers initially assumed that gray-matter damage caused MSA. However, the discovery of oligodendroglial glial cytoplasmic inclusions (GCIs) indicated that damage primarily affects the white matter. […] The chronic alterations in glial cells may impair trophic function between oligodendrocytes and axons and cause secondary neuronal damage. […] Whether the inclusions represent primary lesions or nonspecific secondary markers of cellular injury remains unknown.
#13 Multiple system atrophy – Wikipedia
https://en.wikipedia.org/wiki/Multiple_system_atrophy
Another study investigated the frequency of RFC1 intronic repeat expansions, a phenomenon implicated in CANVAS; a disease with a diagnostic overlap with MSA. […] The study concluded that these repeats were absent in pathologically confirmed MSA, suggesting an alternative genetic cause. […] The disease probably starts with an oligodendrogliopathy. […] It has been proposed that the -synuclein inclusions found in Oligodendrocytes result from the pruning and the engulfment of diseased axonal segments containing aggregated -synuclein, i.e., of Lewy neurites.
#14 The genetic basis of multiple system atrophy | Journal of Translational Medicine | Full Text
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03905-1
Multiple system atrophy (MSA) is a heterogenous, uniformly fatal neurodegenerative -synucleinopathy. […] The underlying pathophysiology is postulated to arise from aberrant -synuclein deposition, mitochondrial dysfunction, oxidative stress and neuroinflammation. […] Although MSA is regarded as a primarily sporadic disease, there is a possible genetic component that is poorly understood. […] This review summarizes current literature on genetic risk factors and potential pathogenic genes and loci linked to both sporadic and familial MSA, and underlines the biological mechanisms that support the role of genetics in MSA. […] Furthermore, we highlight various genetic polymorphisms that modulate MSA risk, including complex gene-gene and gene-environment interactions, which influence the disease phenotype and have clinical significance in both presentation and prognosis.
#15 Understanding Multiple System Atrophyâ Could Genetics Lead the Way? – touchNEUROLOGY
https://touchneurology.com/movement-disorders/journal-articles/understanding-multiple-system-atrophy-could-genetics-lead-the-way/
Multiple system atrophy (MSA) is a progressive, adult-onset, neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia, autonomic failure, and corticospinal tract dysfunction. […] Though MSA has not traditionally been considered a genetic disease, new evidence is emerging supporting some genetic predisposition in many patients. […] More recently there have been some advances in laboratory and translational research in MSA. In particular, genetics of MSA has been a recent topic of interest, and is opening new doors in the understanding of the pathogenesis of MSA. […] Traditionally, most adult-onset neurodegenerative diseases have been considered sporadic rather than genetic in origin. However, more evidence is emerging that many neurodegenerative diseases may have not only a Mendelian pattern of inheritance, but also genes that strongly predispose to the condition.
#16 Multiple System Atrophy: Practice Essentials, Background, Etiology and Pathophysiology
https://emedicine.medscape.com/article/1154583-overview
Single nucleotide polymorphisms (SNPs) at the SNCA locus coding for alpha-synuclein have been identified. G51D mutation in the SNCA locus has been described, but a connection between SCNA locus and MSA disease could not be confirmed. […] Researchers initially assumed that gray-matter damage caused MSA. However, the discovery of oligodendroglial glial cytoplasmic inclusions (GCIs) indicated that damage primarily affects the white matter. […] The chronic alterations in glial cells may impair trophic function between oligodendrocytes and axons and cause secondary neuronal damage. […] Whether the inclusions represent primary lesions or nonspecific secondary markers of cellular injury remains unknown.
#17 Understanding Multiple System Atrophyâ Could Genetics Lead the Way? – touchNEUROLOGY
https://touchneurology.com/movement-disorders/journal-articles/understanding-multiple-system-atrophy-could-genetics-lead-the-way/
Genetics research in MSA is clearly lagging behind that of other -synucleinopathies (Parkinsons disease and dementia with Lewy bodies [DLB]), though recently a few candidate genes have given researchers clues as to the etiology of MSA. […] Mutations and duplications in the -synuclein (SNCA) gene have been clearly linked with -synucleinopathies. […] A few studies found significant associations between variants in the SNCA gene and sporadic cases of clinical MSA […] These findings support a hypothesis that the toxicity of -synuclein plays an important role in the pathogenesis of this disease, and may help to pave the way for therapeutic options. […] The prevalence of GBA mutations among patients with MSA has been studied by a few groups in recent years, and has yielded varied results.
#18 Orphanet: Multiple system atrophy
https://www.orpha.net/en/disease/detail/102
Etiology of MSA is unknown but presence of cytoplasmic aggregates of -synuclein, primarily in oligodendroglia, in combination with neurodegeneration in striatonigral and olivopontocerebellar structures are the pathological hallmark features. […] Mutations in COQ2 (4q21.23) (encoding an enzyme involved in biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased risk for sporadic MSA.
#19 Multiple System Atrophy: Genetic or Epigenetic?
https://www.en-journal.org/journal/view.html?uid=240
Since then, many studies have been performed with the aim to detect disease-causing or disease-linked genes and gene variants. […] Other studies focused on environmental risk factors and epigenetic mechanisms, since MSA shares common features with other neurodegenerative disorders that have proven role of epigenetic modifications in their pathogenesis. […] So far, the underlying mechanisms of MSA etiopathogenesis are still elusive. […] Several familial MSA cases exist, but no hereditable mutations have been found supporting hereditary disease. […] COQ2 mutations have been proposed to associate with familial and sporadic MSA, however this observation could not be replicated in different patient cohorts. […] Investigations of other genetic „hotspots” linked SNCA polymorphisms with an increased risk of developing MSA in Caucasians.
#20
https://www.psp.org/iwanttolearn/prime-of-life-brain-disease/msa
Multiple system atrophy (MSA) is a rare neurodegenerative disorder that has no current known cause or cure. […] Ultimately, it is not yet known why people develop MSA. […] The direct cause of MSA is not fully understood. However, we do know that it has to do with the clumps of alpha-synuclein protein. […] One theory of the cause of MSA is that the clumps of misfolded alpha-synuclein are toxic to the brain. […] There are also theories related to how MSA spreads through the brain. […] In MSA, the alpha-synuclein accumulation and cell loss appear to mainly impact the glial cells, which are the electrically inactive supporting cells of the brain, in addition to the neurons. […] A variant in a gene called GBA, which encodes the enzyme glucocerebrosidase, has been found to be a little more common in people with MSA than in the rest of the population.
#21 Understanding Multiple System Atrophyâ Could Genetics Lead the Way? – touchNEUROLOGY
https://touchneurology.com/movement-disorders/journal-articles/understanding-multiple-system-atrophy-could-genetics-lead-the-way/
Genetics research in MSA is clearly lagging behind that of other -synucleinopathies (Parkinsons disease and dementia with Lewy bodies [DLB]), though recently a few candidate genes have given researchers clues as to the etiology of MSA. […] Mutations and duplications in the -synuclein (SNCA) gene have been clearly linked with -synucleinopathies. […] A few studies found significant associations between variants in the SNCA gene and sporadic cases of clinical MSA […] These findings support a hypothesis that the toxicity of -synuclein plays an important role in the pathogenesis of this disease, and may help to pave the way for therapeutic options. […] The prevalence of GBA mutations among patients with MSA has been studied by a few groups in recent years, and has yielded varied results.
#22 Multiple System Atrophy: Genetic or Epigenetic?
https://www.en-journal.org/journal/view.html?uid=240
Further studies associated gene polymorphisms in IL-1-, IL-1-, IL-8, ICAM-1, -1-antichymotrypsin, tumor necrosis factor genes, SLC1A4, SQSTM1 and EIF4EBPI with MSA predisposition, but failed to detect other disease-causing mutations. […] The genetic background of MSA thereby remains unclear, very much population-specific, and needs to be investigated further. […] Exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, pesticides and other environmental toxins have already been linked to a higher risk of MSA by changing the epigenetic landscape. […] However, the mechanisms of environmental epigenetics are not studied in depth in MSA and need further investigation as supported by the emerging evidence.
#23 Multiple system atrophy – Wikipedia
https://en.wikipedia.org/wiki/Multiple_system_atrophy
Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by tremors, slow movement, muscle rigidity, postural instability (collectively known as parkinsonism), autonomic dysfunction and ataxia. This is caused by progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus, and cerebellum. […] A prion of the alpha-synuclein protein within affected neurons may cause MSA. […] The major filamentous component of Papp-Lantos bodies, glial and neuronal cytoplasmic inclusions, is alpha-synuclein. Mutations in this substance may play a role in the disease. […] One study found a correlation between the deletion of genes in a specific genetic region and the development of MSA in a group of Japanese patients. […] The authors of the study concluded that „Our results indicate that SHC2 gene deletions underlie few, if any, cases of well-characterized MSA in the US population.
#24 Multiple System Atrophy | Baylor Medicine
https://www.bcm.edu/healthcare/specialties/neurology/parkinsons-disease-and-movement-disorders/multiple-system-atrophy
Despite intensive research, the cause of MSA is still unknown. […] There is little evidence that MSA is a genetic disorder, as most patients with MSA have no family history of a neurological disease. […] The pathological findings of MSA are distinct from Parkinson’s disease; however, studies suggest that there may be an overlap between these two disorders. […] Like those with Parkinson’s disease, patients with MSA accumulate the protein, alpha-synuclein, within specific brain cells. […] Abnormalities with the SNCA (alpha synuclein gene) have been found to increase the risk of developing MSA. […] MSA-C has also been reported to be rarely caused by the gene for another disorder of coordination called spinocerebellar ataxia (SCA3).
#25 Multiple System Atrophy: Practice Essentials, Background, Etiology and Pathophysiology
https://emedicine.medscape.com/article/1154583-overview
Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. […] The cause of MSA remains unknown, and no current therapy can reverse or halt progression of the disease. […] The cause of MSA remains unclear, although a history of trauma has been suggested. Pesticide exposure as a causative factor in MSA has been suggested but has not been confirmed statistically. […] Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak. […] There is some evidence of genetic predispositions in Japanese cohorts. Autosomal recessive inheritance and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported.
#26 Multiple system atrophy (MSA) | Types, causes & symptoms
https://cpdonline.co.uk/knowledge-base/care/multiple-system-atrophy/
One small study showed that those affected by MSA had higher rates of toxin exposure such as to metal dust, pesticides, organic solvents and plastics compared with a control group. […] Another study showed that families with more than one person affected by MSA had an autosomal recessive inheritance of the disease, with a single nucleotide polymorphism within the genetic coding for alpha-synuclein. […] However, despite this risk, most cases of MSA are not thought to be directly inherited and occur sporadically. Itâs clear that the causes of MSA are not yet well understood. Ongoing research is focused on identifying the underlying mechanisms that lead to its development and progression.
#27 Multiple system atrophy: Symptoms and treatment
https://www.medicalnewstoday.com/articles/multiple-system-atrophy
Healthcare professionals do not know what causes MSA. Additionally, most cases occur at random, with no family history of the disease. […] Despite the lack of knowledge about what causes it, researchers believe a combination of environmental and genetic factors may play a role in the conditions development and progression. […] Researchers have not identified a specific gene that causes MSA, but some gene variants with links to Parkinsons disease, inflammation, and oxidative stress may raise the risk. […] Currently, there is no definitive evidence of any environmental factors that may raise the risk of MSA. […] MSA also affects the autonomic nervous system, which can result in lightheadedness or fainting and difficulty with bladder control. […] Researchers do not know what causes it.
#28 Multiple system atrophy (MSA) | Types, causes & symptoms
https://cpdonline.co.uk/knowledge-base/care/multiple-system-atrophy/
One small study showed that those affected by MSA had higher rates of toxin exposure such as to metal dust, pesticides, organic solvents and plastics compared with a control group. […] Another study showed that families with more than one person affected by MSA had an autosomal recessive inheritance of the disease, with a single nucleotide polymorphism within the genetic coding for alpha-synuclein. […] However, despite this risk, most cases of MSA are not thought to be directly inherited and occur sporadically. Itâs clear that the causes of MSA are not yet well understood. Ongoing research is focused on identifying the underlying mechanisms that lead to its development and progression.
#29 Multiple System Atrophy: Genetic or Epigenetic?
https://www.en-journal.org/journal/view.html?uid=240
Further studies associated gene polymorphisms in IL-1-, IL-1-, IL-8, ICAM-1, -1-antichymotrypsin, tumor necrosis factor genes, SLC1A4, SQSTM1 and EIF4EBPI with MSA predisposition, but failed to detect other disease-causing mutations. […] The genetic background of MSA thereby remains unclear, very much population-specific, and needs to be investigated further. […] Exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, pesticides and other environmental toxins have already been linked to a higher risk of MSA by changing the epigenetic landscape. […] However, the mechanisms of environmental epigenetics are not studied in depth in MSA and need further investigation as supported by the emerging evidence.
#30
https://www.psp.org/iwanttolearn/prime-of-life-brain-disease/msa
Variants in the gene encoding COQ2, an enzyme that helps in the production of coenzyme Q10, which is important to the production of energy by brain cells, were found in family members with MSA in two Japanese families where multiple members had MSA. […] However, one study done in North America found that occupational exposure to organic solvents, plastic monomers, metals, and pesticides was slightly higher in people with MSA. […] There is evidence of higher levels of inflammation in the brains of people with MSA, though it remains unclear whether this is a cause of the disease or a side effect of the disease process.
#31 Multiple System Atrophy: Practice Essentials, Background, Etiology and Pathophysiology
https://emedicine.medscape.com/article/1154583-overview
Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. […] The cause of MSA remains unknown, and no current therapy can reverse or halt progression of the disease. […] The cause of MSA remains unclear, although a history of trauma has been suggested. Pesticide exposure as a causative factor in MSA has been suggested but has not been confirmed statistically. […] Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak. […] There is some evidence of genetic predispositions in Japanese cohorts. Autosomal recessive inheritance and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported.
#32 Multiple system atrophy (MSA) | Types, causes & symptoms
https://cpdonline.co.uk/knowledge-base/care/multiple-system-atrophy/
Multiple system atrophy is commonly abbreviated to MSA and it affects adult men and women. Itâs a rare and progressive neurological disorder that affects the autonomic nervous system. It is caused by the degeneration or atrophy of the nerve cells. […] The exact cause of multiple system atrophy is not known. It is believed to be a combination of genetic and environmental factors. Itâs a rare disorder and is thought to be due to the effects of an abnormal accumulation of a protein called alpha-synuclein in certain areas of the brain which leads to the degeneration of nerve cells. […] An old theory is that there has previously been some trauma in the brainâs grey matter. However, this theory is now largely not thought to be the case. There has been some research that has shown links with environmental factors such as toxins being higher in those affected by MSA compared with those unaffected.
#33 Multiple System Atrophy: Genetic or Epigenetic?
https://www.en-journal.org/journal/view.html?uid=240
Further studies associated gene polymorphisms in IL-1-, IL-1-, IL-8, ICAM-1, -1-antichymotrypsin, tumor necrosis factor genes, SLC1A4, SQSTM1 and EIF4EBPI with MSA predisposition, but failed to detect other disease-causing mutations. […] The genetic background of MSA thereby remains unclear, very much population-specific, and needs to be investigated further. […] Exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, pesticides and other environmental toxins have already been linked to a higher risk of MSA by changing the epigenetic landscape. […] However, the mechanisms of environmental epigenetics are not studied in depth in MSA and need further investigation as supported by the emerging evidence.
#34 Understanding Multiple System Atrophyâ Could Genetics Lead the Way? – touchNEUROLOGY
https://touchneurology.com/movement-disorders/journal-articles/understanding-multiple-system-atrophy-could-genetics-lead-the-way/
This study certainly indicates that further study of the relationship between GBA and MSA is required. […] More recent efforts in the field of MSA genetics have revealed several candidate genes that may be involved in the pathogenesis of the disease. […] The pathogenesis of MSA remains an enigma, though it is becoming clear that genetic associations exist. […] Many mechanisms for the development and propagation of MSA have been postulated, including impaired elimination of -synuclein within the cell, mitochondrial dysfunction, direct toxicity of -synuclein, oxidative stress, and neuroinflammation. […] We are hopeful that genetic associations may give us further clues into the pathogenesis of MSA, as well as targets for therapeutic interventions. […] It is clear that none of the genetic associations discussed above confer a high penetrance for development of MSA; rather they likely create a pre-disposition for this rare and devastating disease.
#35 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
The temporal sequence of pathogenic events is still obscure and it is not clear which of the proposed causative mechanisms (e.g. protein accumulation, mitochondrial dysfunction, inflammation) represents the primary episode which triggers the whole pathogenic cascade. […] The peculiar oligodendroglial pathological presentation of MSA has induced many investigators to hypothesize that the primitive cause of the disease has to be related to -syn accumulation in this cellular subtype and this is also the rationale underlying MSA transgenic mouse models. […] On the other hand, recent studies are supportive for a causative role of mitochondria in the pathogenesis of MSA. […] It is also interesting to highlight that one of the first in vivo models of the disease (not used anymore) has been obtained by administering the succinate dehydrogenase (respiratory chain complex II) inhibitor 3-nitroproprionic acid (3-NP acid) to animals for its ability to cause a striatal lesion.
#36
https://www.psp.org/iwanttolearn/prime-of-life-brain-disease/msa
Variants in the gene encoding COQ2, an enzyme that helps in the production of coenzyme Q10, which is important to the production of energy by brain cells, were found in family members with MSA in two Japanese families where multiple members had MSA. […] However, one study done in North America found that occupational exposure to organic solvents, plastic monomers, metals, and pesticides was slightly higher in people with MSA. […] There is evidence of higher levels of inflammation in the brains of people with MSA, though it remains unclear whether this is a cause of the disease or a side effect of the disease process.
#37
https://www.psp.org/iwanttolearn/prime-of-life-brain-disease/msa
Variants in the gene encoding COQ2, an enzyme that helps in the production of coenzyme Q10, which is important to the production of energy by brain cells, were found in family members with MSA in two Japanese families where multiple members had MSA. […] However, one study done in North America found that occupational exposure to organic solvents, plastic monomers, metals, and pesticides was slightly higher in people with MSA. […] There is evidence of higher levels of inflammation in the brains of people with MSA, though it remains unclear whether this is a cause of the disease or a side effect of the disease process.
#38 The genetic basis of multiple system atrophy | Journal of Translational Medicine | Full Text
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03905-1
Neuroinflammation has been a purported mechanism in the pathogenesis of MSA. […] The consequent microglial activation, cytokine and chemokine release, and pro-inflammatory conditions are thought to accelerate -synuclein aggregation and oligodendroglial apoptosis. […] Genetic studies have allowed us to understand potential genetic factors that underpin the disease. […] Current studies have suggested possible associations between MSA risk and a wide range of gene mutations and polymorphisms. […] However, thus far no monogenic forms of MSA have been identified. […] Multinational and multicenter studies with longitudinal follow up data will be helpful in identifying rare gene variants with small effect sizes and delineating heterogeneity between various age, sex and ethnic subgroups. […] Functional studies in both animal and human models of the various identified genetic variants/mutations can identify novel pathophysiologic clues which may lead to development of disease-modifying therapeutic targets.
#39 Multiple System Atrophy: Practice Essentials, Background, Etiology and Pathophysiology
https://emedicine.medscape.com/article/1154583-overview
Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. […] The cause of MSA remains unknown, and no current therapy can reverse or halt progression of the disease. […] The cause of MSA remains unclear, although a history of trauma has been suggested. Pesticide exposure as a causative factor in MSA has been suggested but has not been confirmed statistically. […] Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak. […] There is some evidence of genetic predispositions in Japanese cohorts. Autosomal recessive inheritance and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported.
#40 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
A new field of investigation derives from the recent description of a prion-like spreading pathology of -syn in MSA. […] Recent studies have pointed out the role of specific -syn strains in the pathogenesis of synucleinopathies. […] Impaired protein degradation may also be involved in -syn accumulation, as suggested by the description of a possible role of autophagic and proteasomal dysfunction in the disease. […] The finding of an increased iron level in specific brain regions of MSA patients has led to the hypothesis that iron metabolism dysregulation may play a role in the pathogenesis of the disease. […] Although several efforts have been dedicated to unravelling the causes of MSA, the precise pathogenic mechanisms underlying this disorder still have to be elucidated. […] The peculiar neuropathological pattern of the disease, characterized by -syn accumulation in oligodendrocytes, has led many investigators to focus on this particular aspect and to hypothesize that MSA primarily represents an oligodendrogliopathy, with a secondary neuronal involvement.
#41 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
A new field of investigation derives from the recent description of a prion-like spreading pathology of -syn in MSA. […] Recent studies have pointed out the role of specific -syn strains in the pathogenesis of synucleinopathies. […] Impaired protein degradation may also be involved in -syn accumulation, as suggested by the description of a possible role of autophagic and proteasomal dysfunction in the disease. […] The finding of an increased iron level in specific brain regions of MSA patients has led to the hypothesis that iron metabolism dysregulation may play a role in the pathogenesis of the disease. […] Although several efforts have been dedicated to unravelling the causes of MSA, the precise pathogenic mechanisms underlying this disorder still have to be elucidated. […] The peculiar neuropathological pattern of the disease, characterized by -syn accumulation in oligodendrocytes, has led many investigators to focus on this particular aspect and to hypothesize that MSA primarily represents an oligodendrogliopathy, with a secondary neuronal involvement.
#42 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
Therefore, it is intriguing to hypothesize that MSA represents a multifactorial disease caused by the combined effect of multiple hits. […] The importance of understanding the molecular mechanisms of the disease has not only purely speculative purposes, but also finds practical applications in identifying new biomarkers and therapeutic approaches.
#43
https://www.aurorahealthcare.org/services/neuroscience/neurology/neurological-conditions/multiple-system-atrophy
Multiple system atrophy (MSA) occurs due to various factors that contribute to its development. […] Scientists believe it results from a combination of genetic predispositions, environmental influences and other risk factors. […] While the exact cause remains unclear, researchers have made significant strides in unraveling its origins. […] Genetics plays a role in multiple system atrophy development. […] Certain genetic variations may increase a person’s susceptibility to developing this disease, but they typically interact with other factors to trigger the disease. […] These genetic factors affect the functioning of proteins within cells, leading to abnormal protein buildup in the brain a hallmark of multiple system atrophy. […] Several factors may increase an individual’s risk of developing multiple system atrophy.
#44 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
Therefore, it is intriguing to hypothesize that MSA represents a multifactorial disease caused by the combined effect of multiple hits. […] The importance of understanding the molecular mechanisms of the disease has not only purely speculative purposes, but also finds practical applications in identifying new biomarkers and therapeutic approaches.
#45 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
The temporal sequence of pathogenic events is still obscure and it is not clear which of the proposed causative mechanisms (e.g. protein accumulation, mitochondrial dysfunction, inflammation) represents the primary episode which triggers the whole pathogenic cascade. […] The peculiar oligodendroglial pathological presentation of MSA has induced many investigators to hypothesize that the primitive cause of the disease has to be related to -syn accumulation in this cellular subtype and this is also the rationale underlying MSA transgenic mouse models. […] On the other hand, recent studies are supportive for a causative role of mitochondria in the pathogenesis of MSA. […] It is also interesting to highlight that one of the first in vivo models of the disease (not used anymore) has been obtained by administering the succinate dehydrogenase (respiratory chain complex II) inhibitor 3-nitroproprionic acid (3-NP acid) to animals for its ability to cause a striatal lesion.
#46 Multiple system atrophy – parkinsonian type: MedlinePlus Medical EncyclopediaLock
https://medlineplus.gov/ency/article/000757.htm
The cause of MSA-P is unknown. The affected areas of the brain overlap with areas affected by Parkinson disease, with similar symptoms. For this reason, this subtype of MSA is called parkinsonian. […] MSA-P is most often diagnosed in men older than 60.
#47
https://www.aurorahealthcare.org/services/neuroscience/neurology/neurological-conditions/multiple-system-atrophy
Age is a significant risk factor with the condition typically appearing in adulthood, usually around the ages of 50-60. […] Additionally, men seem to be more susceptible to multiple system atrophy than women. […] Other risk factors include a history of certain neurological conditions, such as Parkinson’s disease.
#48 MSA-C – National Ataxia Foundation
https://www.ataxia.org/msa-c/
Multiple System Atrophy Cerebellar type (MSA-C) is a rare, sporadic neurodegenerative disorder that causes difficulties with balance, coordination, and autonomic functions of the body. […] MSA-C is a sporadic disease, meaning that it happens infrequently in the population without known genetic or environmental causes. Research is being done to better understand why MSA-C occurs. […] Multiple System Atrophy is a rare neurodegenerative disorder. Approximately 3 in 100,000 people will develop MSA, but the frequency and subtype of MSA varies considerably based on geographical location and ethnic background. […] MSA-C tends to be less common than MSA-P.
#49 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
Therefore, it is intriguing to hypothesize that MSA represents a multifactorial disease caused by the combined effect of multiple hits. […] The importance of understanding the molecular mechanisms of the disease has not only purely speculative purposes, but also finds practical applications in identifying new biomarkers and therapeutic approaches.
#50 The genetic basis of multiple system atrophy | Journal of Translational Medicine | Full Text
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03905-1
Neuroinflammation has been a purported mechanism in the pathogenesis of MSA. […] The consequent microglial activation, cytokine and chemokine release, and pro-inflammatory conditions are thought to accelerate -synuclein aggregation and oligodendroglial apoptosis. […] Genetic studies have allowed us to understand potential genetic factors that underpin the disease. […] Current studies have suggested possible associations between MSA risk and a wide range of gene mutations and polymorphisms. […] However, thus far no monogenic forms of MSA have been identified. […] Multinational and multicenter studies with longitudinal follow up data will be helpful in identifying rare gene variants with small effect sizes and delineating heterogeneity between various age, sex and ethnic subgroups. […] Functional studies in both animal and human models of the various identified genetic variants/mutations can identify novel pathophysiologic clues which may lead to development of disease-modifying therapeutic targets.
#51 Understanding Multiple System Atrophyâ Could Genetics Lead the Way? – touchNEUROLOGY
https://touchneurology.com/movement-disorders/journal-articles/understanding-multiple-system-atrophy-could-genetics-lead-the-way/
This study certainly indicates that further study of the relationship between GBA and MSA is required. […] More recent efforts in the field of MSA genetics have revealed several candidate genes that may be involved in the pathogenesis of the disease. […] The pathogenesis of MSA remains an enigma, though it is becoming clear that genetic associations exist. […] Many mechanisms for the development and propagation of MSA have been postulated, including impaired elimination of -synuclein within the cell, mitochondrial dysfunction, direct toxicity of -synuclein, oxidative stress, and neuroinflammation. […] We are hopeful that genetic associations may give us further clues into the pathogenesis of MSA, as well as targets for therapeutic interventions. […] It is clear that none of the genetic associations discussed above confer a high penetrance for development of MSA; rather they likely create a pre-disposition for this rare and devastating disease.
#52 The genetic basis of multiple system atrophy | Journal of Translational Medicine | Full Text
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03905-1
Neuroinflammation has been a purported mechanism in the pathogenesis of MSA. […] The consequent microglial activation, cytokine and chemokine release, and pro-inflammatory conditions are thought to accelerate -synuclein aggregation and oligodendroglial apoptosis. […] Genetic studies have allowed us to understand potential genetic factors that underpin the disease. […] Current studies have suggested possible associations between MSA risk and a wide range of gene mutations and polymorphisms. […] However, thus far no monogenic forms of MSA have been identified. […] Multinational and multicenter studies with longitudinal follow up data will be helpful in identifying rare gene variants with small effect sizes and delineating heterogeneity between various age, sex and ethnic subgroups. […] Functional studies in both animal and human models of the various identified genetic variants/mutations can identify novel pathophysiologic clues which may lead to development of disease-modifying therapeutic targets.
#53 Multiple System Atrophy-D Maybe Something AltogetherâDifferent
https://practicalneurology.com/articles/2018-mar-apr/multiple-system-atrophy-d-maybe-something-altogetherdifferent
The prion hypothesis, a theory that has been gaining support, was presented as the plenary lecture. Dr. Stanley Prusiner discussed experiments in which -synuclein samples from the brains of 14 patients who had MSA were transmitted to homozygous mice. After an incubation of 120 days, the mice developed neurodegeneration that was accompanied by deposition of -synuclein in cell bodies and axons. Control, sham-infected mice as well as those infected with -synuclein from the brains of patients who had PD did not develop neurodegeneration. Although controversial, these data are compelling and support the idea that despite clinical and pathologic similarities, MSA and PD are distinct points on a spectrum of neurodegeneration. […] As with most neurodegenerative diseases, we are at a fork in the road, with one path leading toward disease-modifying treatments and the other to symptomatic management. For the latter, currently in phase 2 trials, TD-9855 is being studied for the treatment of neurogenic orthostatic hypotension, as a daily-dose compound with vasogenic tone properties. For disease modification, studies of possible therapies run the gamut from autophagy, to active immunization, vaccination, and stem cells. […] Although it is likely that MSA and PD will always be intertwined, MSA is emerging as a distinct pathology.
#54 Multiple System Atrophy
https://www.brainfacts.org/diseases-and-disorders/neurological-disorders-az/diseases-a-to-z-from-ninds/multiple-system-atrophy
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by symptoms of autonomic nervous system failure such as fainting spells and bladder control problems, combined with motor control symptoms such as tremor, rigidity, and loss of muscle coordination. […] Although what causes MSA is unknown, the disorder’s symptoms reflect the loss of nerve cells in several different areas in the brain and spinal cord that control the autonomic nervous system and coordinate muscle movements. […] The loss of nerve cells may be due to the buildup of a protein called alpha-synuclein in the cells that support nerve cells in the brain. […] Researchers hope to learn why alpha-synuclein buildup occurs in MSA and Parkinsons disease, and how to prevent it. […] Drugs that reduce the abnormal alpha-synuclein buildup may be promising treatments for MSA.
#55 Multiple System Atrophy
https://www.brainfacts.org/diseases-and-disorders/neurological-disorders-az/diseases-a-to-z-from-ninds/multiple-system-atrophy
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by symptoms of autonomic nervous system failure such as fainting spells and bladder control problems, combined with motor control symptoms such as tremor, rigidity, and loss of muscle coordination. […] Although what causes MSA is unknown, the disorder’s symptoms reflect the loss of nerve cells in several different areas in the brain and spinal cord that control the autonomic nervous system and coordinate muscle movements. […] The loss of nerve cells may be due to the buildup of a protein called alpha-synuclein in the cells that support nerve cells in the brain. […] Researchers hope to learn why alpha-synuclein buildup occurs in MSA and Parkinsons disease, and how to prevent it. […] Drugs that reduce the abnormal alpha-synuclein buildup may be promising treatments for MSA.
#56 Multiple System Atrophy | National Institute of Neurological Disorders and Stroke
https://www.ninds.nih.gov/health-information/disorders/multiple-system-atrophy
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by a combination of symptoms that affect both the central nervous system (which controls how a person moves), and the autonomic nervous system, which controls involuntary functions such as blood pressure or digestion. […] The cause of MSA is unknown. The vast majority of cases are sporadic, meaning they occur at random. […] Certain genetic variants have been reported to influence MSA risk, including genes related to oxidative stress, inflammation, and other genes related to Parkinson’s disease. However, a specific gene responsible for causing MSA has not yet been identified, and the genetic basis of MSA is not well understood. […] It is believed that a combination of genetic and environmental factors likely contributes to the development and progression of the disease.
#57 Multiple System Atrophy | Penn State Health
https://www.pennstatehealth.org/services-treatments/multiple-system-atrophy
Multiple system atrophy (MSA) is a rare, progressive neurological disorder that affects parts of the brain responsible for controlling movement and involuntary processes, such as blood pressure, heartbeat, urination, bowel movement and sleep patterns. […] Currently, the exact causes of MSA are unknown. Like many other diseases, it may not have a single cause, but a combination of genetic, environmental and behavioral factors. […] Along with researchers around the world, the clinicians and scientists at Penn State College of Medicines Translational Brain Research Center are devoted to identifying the causes of MSA and developing better diagnostic tools through partnership with the National Institute of Neurological Disorders and Stroke (NINDS) Parkinsons Disease Biomarkers Program (PDBP) and clinical trials.
#58 Multiple System Atrophy (MSA) – Neurologic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/neurologic-disorders/autonomic-nervous-system/multiple-system-atrophy-msa
Etiology of multiple system atrophy is unknown, but neuronal degeneration occurs in several areas of the brain; the area and amount damaged determine initial symptoms. A characteristic finding is cytoplasmic inclusion bodies containing alpha-synuclein within oligodendroglial cells. […] Multiple system atrophy is a synucleinopathy (due to synuclein deposition); synuclein can also accumulate in patients with Parkinson disease, pure autonomic failure, or dementia with Lewy bodies. Synuclein is a neuronal and glial cell protein that can aggregate into insoluble fibrils and form Lewy bodies.
#59 Multiple system atrophy: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/multiple-system-atrophy/
Multiple system atrophy is a complex condition that is likely caused by the interaction of multiple genetic, environmental, and lifestyle factors. Some of these factors have been identified, but many remain unknown. […] Changes in several genes are being studied as possible risk factors for multiple system atrophy. The genetic risk factors with the most evidence are variants in the SNCA and COQ2 genes. […] It is unclear how changes in the SNCA or COQ2 gene increase the risk of developing multiple system atrophy. […] Researchers have also examined environmental factors that could contribute to the risk of multiple system atrophy. Initial studies suggested that exposure to solvents, certain types of plastic or metal, and other potential toxins might be associated with the condition. However, these associations have not been confirmed.
#60 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6
Therefore, it is intriguing to hypothesize that MSA represents a multifactorial disease caused by the combined effect of multiple hits. […] The importance of understanding the molecular mechanisms of the disease has not only purely speculative purposes, but also finds practical applications in identifying new biomarkers and therapeutic approaches.
#61 Multiple System Atrophy | Peter O’Donnell Jr. Brain Institute | Condition | UT Southwestern Medical Center
https://utswmed.org/conditions-treatments/multiple-system-atrophy/
Multiple system atrophy (MSA), formerly known as Shy-Drager syndrome, is a rare, progressive neurodegenerative disorder that causes deterioration and shrinkage of the parts of the brain that regulate internal body functions, digestion, and motor control. Theres no known cause for these brain changes. […] While there is no cure for MSA or specific treatments to slow its progression, research has brought us closer to identifying the cause of MSA, which is the first step toward finding a cure.