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Alpha-synuclein transgenic mice: Relevance to multiple system atrophy

Authors

  • Gwenaelle Fillon MSc,

    1. Laboratory of Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University of Munich, Germany
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  • Philipp J. Kahle PhD

    Corresponding author
    1. Laboratory of Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University of Munich, Germany
    • Laboratory of Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University of Munich, Schillerstrasse 44, 80336 Munich, Germany
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Abstract

(Oligodendro)glial cytoplasmic inclusions composed of the protein α-synuclein (αSYN) are the neuropathological hallmark lesions of multiple system atrophy (MSA). The recent generation of transgenic mouse models of oligodendroglial α-synucleinopathy has enabled studies to investigate how αSYN causally contributes to MSA neuropathology. Moreover, human disease-specific pathological modifications of αSYN 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 α1B-adrenergic receptor mutant showed evidence of αSYN pathology in oligodendrocytes, adding dysregulated adrenergic neurotransmission to the list of potential risk factors of MSA. Finally, a double-transgenic mouse model expressing both αSYN and tau revealed synergistic fibrillization of these two proteins, providing an animal model for the not uncommon neuropathological finding of concomitant α-synucleinopathy and tauopathy within oligodendrocytes. Despite the progress made modeling MSA neuropathology in the transgenic mouse models, the molecular mechanism of how αSYN 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. © 2005 Movement Disorder Society

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