Alpha-synuclein transgenic mice: Relevance to multiple system atrophy

(Oligodendro)glial cytoplasmic inclusions composed of the protein alpha-synuctein (alpha SYN) are the neuropathological hallmark lesions of multiple system atrophy (MSA). The recent generation of transgenic mouse models of oligodendroglial alpha-synucleinopathy has enabled studies to investigate how aSYN causally contributes to MSA neuropathology. Moreover, human disease-specific pathological modifications of alpha SYN were recapitulated in transgenic mice, including insolubility, phosphorylation at serine-129, and ubiquitination. Thus, the transgenic mice will be useful tools to assess cellular risk factors, such as protein folding stress, protein kinase hyperactivity, and failure of the ubiquitin-proteasome system. Moreover, transgenic mice expressing a hyperactive alpha(1B)-adrenergic receptor mutant showed evidence of alpha SYN pathology in oligodendrocytes, adding dysregulated adrenergic neuro-transmission to the list of potential risk factors of MSA. Finally, a double-transgenic mouse model expressing both alpha SYN and tau revealed synergistic fibrillization of these two proteins, providing an animal model for the not uncommon neuropathological finding of concomitant alpha-synucleinopathy and tauopathy within oligodendrocytes. Despite the progress made modeling MSA neuropathology in the transgenic mouse models, the molecular mechanism of how aSYN aggregation in oligodendrocytes causes neurodegeneration remains to be established. Moreover, it will be important to understand what defines the predilection sites most severely affected by striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C), respectively. (c) 2005 Movement Disorder Society.