Abstract
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), and dysautonomia with cerebellar ataxia or parkinsonian motor features. Isolated autonomic dysfunction with predominant genitourinary dysfunction and orthostatic hypotension and REM sleep behavior disorder are common characteristics of a prodromal phase, which may occur years prior to motor-symptom onset. MSA is a unique synucleinopathy, in which alpha-synuclein (aSyn) accumulates and forms insoluble inclusions in the cytoplasm of oligodendrocytes, termed glial cytoplasmic inclusions (GCIs). The origin of, and precise mechanism by which aSyn accumulates in MSA are unknown, and, therefore, disease-modifying therapies to halt or slow the progression of MSA are currently unavailable. For these reasons, much focus in the field is concerned with deciphering the complex neuropathological mechanisms by which MSA begins and progresses through the course of the disease. This review focuses on the history, etiopathogenesis, neuropathology, as well as cell and animal models of MSA.
Highlights
Historical review of MSAMultiple system atrophy (MSA) is a rare, universally fatal, and progressive neurodegenerative disease, clinically characterized by parkinsonian, cerebellar, and dysautonomic features in any combination
The disease we call MSA was separated into three distinct diseases based on symptomatology including Shy–Drager syndrome as well as neuropathology including striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA)
The distinguished movement disorders specialist Professor Niall Quinn, described clinicians over decades approaching MSA like “blindfolded men examining different parts of an elephant and coming away with different impressions of the nature of the beast” (Quinn 1989). It was not until 1969 that Graham and Oppenheimer united these different parts of the “beast”- olivopontocerebellar atrophy, Shy–Drager syndrome, and striatonigral degeneration—as a single disease, stating “there is a group of progressive neurological conditions, most often arising during middle life, with symptoms and signs of lesions affecting several central nervous structures...what is needed is a general term to cover this collection of overlapping progressive pre-senile multi-system degenerations
Summary
Multiple system atrophy (MSA) is a rare, universally fatal, and progressive neurodegenerative disease, clinically characterized by parkinsonian, cerebellar, and dysautonomic features in any combination. The distinguished movement disorders specialist Professor Niall Quinn, described clinicians over decades approaching MSA like “blindfolded men examining different parts of an elephant and coming away with different impressions of the nature of the beast” (Quinn 1989) It was not until 1969 that Graham and Oppenheimer united these different parts of the “beast”- olivopontocerebellar atrophy, Shy–Drager syndrome, and striatonigral degeneration—as a single disease, stating “there is a group of progressive neurological conditions, most often arising during middle life, with symptoms and signs of lesions affecting several central nervous structures...what is needed is a general term to cover this collection of overlapping progressive pre-senile multi-system degenerations. While an exciting paradigm shift in understanding synucleinopathies, the strain differences need to be more closely examined and reproduced as in vitro amplification of prion-like proteins do not always recapitulate how they behave in vivo
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