Models of multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a neurodegenerative disease with diverse clinical manifestations, including parkinsonism, cerebellar syndrome, and autonomic failure. Pathologically, MSA is characterized by glial cytoplasmic inclusions in oligodendrocytes, which contain fibrillary forms of α-synuclein. MSA is categorized as one of the αsynucleinopathy, and α-synuclein aggregation is thought to be the culprit of the disease pathogenesis. Studies on MSA pathogenesis are scarce relative to studies on the pathogenesis of other synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies. However, recent developments in cellular and animal models of MSA, especially α-synuclein transgenic models, have driven advancements in research on this disease. Here, we review the currently available models of MSA, which include toxicant-induced animal models, α-synuclein-overexpressing cellular models, and mouse models that express α-synuclein specifically in oligodendrocytes through cell type-specific promoters. We will also discuss the results of studies in recently developed transmission mouse models, into which MSA brain extracts were intracerebrally injected. By reviewing the findings obtained from these model systems, we will discuss what we have learned about the disease and describe the strengths and limitations of the models, thereby ultimately providing direction for the design of better models and future research.

Inflammation in Experimental Models of α‐Synucleinopathies

“…These models do not recapitulate the α‐synuclein glial cell inclusions that are pathognomonic of MSA and are now rarely used. There are 3 transgenic mouse models of MSA that vary based on the promoter used, and these mutants have been used to form the basis of the current immunotherapy and immunotherapy plus anti‐inflammatory approaches 43 . We 44 and others 45 have recently created models of the MSA parkinsonian form and MSA cerebellar variant using viral vectors that overexpress α‐synuclein in oligodendroglial cells.…”

“…The MSA parkinsonian form has previously been modeled by toxins such a 3-nitroprioprionic acid, a complex II inhibitor that results in striatal degeneration, or combined lesions of the nigrostriatal system with 6-hydroxydopamine and the striatum with quinolinic acid. 43 These models do not recapitulate the α-synuclein glial cell inclusions that are pathognomonic of MSA and are now rarely used. There are 3 transgenic mouse models of MSA that vary based on the promoter used, and these mutants have been used to form the basis of the current immunotherapy and immunotherapy plus anti-inflammatory approaches.…”

“…There are 2 different forms of MSA: MSA parkinsonian form and MSA cerebellar variant. The MSA parkinsonian form has previously been modeled by toxins such a 3‐nitroprioprionic acid, a complex II inhibitor that results in striatal degeneration, or combined lesions of the nigrostriatal system with 6‐hydroxydopamine and the striatum with quinolinic acid 43 . These models do not recapitulate the α‐synuclein glial cell inclusions that are pathognomonic of MSA and are now rarely used.…”

Alpha-Synuclein Inclusion Formation in Human Oligodendrocytes

“…Multiple system atrophy (MSA) is a relatively rare, sporadic adult-onset neurodegenerative disorder. It is characterized by Parkinson-like motor symptoms, such as bradykinesia, rigidity, and postural instability, and non-motor symptoms of sleep and cognitive disorders, respiratory problems, and emotional/behavioral symptoms ( Benrud-Larson et al ., 2005 ; Jecmenica-Lukic et al ., 2012 ; Lee et al ., 2019 ). The main pathological characteristics of MSA are extended neuronal death and gliosis in several areas of the central nervous system.…”

“…Animal models of MSA utilize the toxins injected in the brain or the transgenic expression of α-synuclein with oligodendrocyte-specific promoters [ reviewed in Lee et al . (2019) ].…”