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(American Journal of Pathology. 2005;166:869-876.)
© 2005 American Society for Investigative Pathology

Oxidative Stress in Transgenic Mice with Oligodendroglial {alpha}-Synuclein Overexpression Replicates the Characteristic Neuropathology of Multiple System Atrophy

Nadia Stefanova*, Markus Reindl*, Manuela Neumann{dagger}, Christian Haass{ddagger}, Werner Poewe*, Philipp J. Kahle{ddagger} and Gregor K. Wenning*

From the Clinical Department of Neurology,* Neurological Research Laboratory, Innsbruck Medical University, Innsbruck, Austria; and the Department of Neuropathology{dagger} and the Department of Metabolic Biochemistry,{ddagger} Laboratory for Alzheimer’s and Parkinson’s Disease Research, Ludwig Maximilians University, Munich, Germany

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism unresponsive to dopaminergic therapy, cerebellar ataxia, and dysautonomia. Neuropathology shows a characteristic neuronal multisystem degeneration that is associated with widespread oligodendroglial {alpha}-synuclein ({alpha}-SYN) inclusions. Presently no animal model completely replicates the specific neuropathology of MSA. Here we investigated the behavioral and pathological features resulting from oligodendroglial {alpha}-SYN overexpression in transgenic mice exposed to mitochondrial inhibition by 3-nitropropionic acid. In transgenic mice 3-nitropropionic acid induced or augmented motor deficits that were associated with MSA-like pathology including striatonigral degeneration and olivopontocerebellar atrophy. Widespread astrogliosis and microglial activation were also observed in the presence of {alpha}-SYN in oligodendrocytes. Our results indicate that combined mitochondrial inhibition and overexpression of oligodendroglial {alpha}-SYN generates a novel model of MSA that may be useful for evaluating both pathogenesis and treatment strategies.




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