Age-related motor dysfunction and neuropathology in a transgenic mouse model of multiple system atrophy.
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a progressive degeneration of the striatonigral, olivo-ponto-cerebellar, and autonomic systems. Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein represent the hallmark of MSA and are recapitulated in mice expressing alpha-synuclein in oligodendrocytes. To assess if oligodendroglial expression of human wild-type alpha-synuclein in mice (proteolipid promoter, PLP-SYN) could be associated with age-related deficits, PLP-SYN and wild-type mice were assessed for motor function, brain morphometry, striatal levels of dopamine and metabolites, dopaminergic loss, and distribution of GCIs. PLP-SYN displayed age-related impairments on a beam-traversing task. MRI revealed a significantly smaller brain volume in PLP-SYN mice at 12 months, which further decreased at 18 months together with increased volume of ventricles and cortical atrophy. The distribution of GCIs was reminiscent of MSA with a high burden in the basal ganglia. Mild dopaminergic cell loss was associated with decreased dopamine turnover at 18 months. These data indicate that PLP-SYN mice may recapitulate some of the progressive features of MSA and deliver endpoints for the evaluation of therapeutic strategies.
Institut des Maladies Neurodégénératives, Université de Bordeaux, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
P O
PO
Fernagut
W G
WG
Meissner
M
M
Biran
M
M
Fantin
F
F
Bassil
J M
JM
Franconi
F
F
Tison
D000367:Age Factors; D000818:Animals; D001284:Atrophy; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D002552:Cerebral Ventricles / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009069:Movement Disorders / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D019578:Multiple System Atrophy / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D051844:alpha-Synuclein; D004298:Dopamine
alpha-synuclein; magnetic resonance imaging; motor behavior; multiple system atrophy