Alpha-synuclein transgenic mice: relevance to multiple system atrophy.
(Oligodendro)glial cytoplasmic inclusions composed of the protein alpha-synuclein (alphaSYN) 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 alphaSYN causally contributes to MSA neuropathology. Moreover, human disease-specific pathological modifications of alphaSYN 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 alphaSYN pathology in oligodendrocytes, adding dysregulated adrenergic neurotransmission to the list of potential risk factors of MSA. Finally, a double-transgenic mouse model expressing both alphaSYN 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 alphaSYN 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.
Fillon
Gwenaelle
G
Laboratory of Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University of Munich, Germany.
Kahle
Philipp J
PJ
D000818:Animals; D004195:Disease Models, Animal; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000235:genetics* / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics
D051844:alpha-Synuclein; D016875:tau Proteins