Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy.
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.
Stefanova
Nadia
N
Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35 A-6020, Innsbruck, Austria.
Reindl
Markus
M
Neumann
Manuela
M
Haass
Christian
C
Poewe
Werner
W
Kahle
Philipp J
PJ
Wenning
Gregor K
GK
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009068:Movement; D009069:Movement Disorders / Q000235:genetics; D019578:Multiple System Atrophy / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D009574:Nitro Compounds; D009836:Oligodendroglia / Q000378:metabolism*; D018384:Oxidative Stress; D011422:Propionates / Q000494:pharmacology; D051843:Synucleins; D013997:Time Factors; D051844:alpha-Synuclein; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D009419:Nerve Tissue Proteins; D009574:Nitro Compounds; D011422:Propionates; D051843:Synucleins; D051844:alpha-Synuclein; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C497605:Snca protein, mouse; C015392:3-nitropropionic acid
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