Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy.
Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of alpha-synuclein (alpha-syn) in oligodendrocytes. To better understand the mechanisms of neurodegeneration and the role of alpha-syn accumulation in oligodendrocytes in the pathogenesis of MSA, we generated transgenic mouse lines expressing human (h) alpha-syn under the control of the murine myelin basic protein promoter. Transgenic mice expressing high levels of halpha-syn displayed severe neurological alterations and died prematurely at 6 months of age. Furthermore, mice developed progressive accumulation of halpha-syn-immunoreactive inclusions in oligodendrocytes along the axonal tracts in the brainstem, basal ganglia, cerebellum, corpus callosum, and neocortex. The inclusions also reacted with antibodies against phospho-serine (129) halpha-syn and ubiquitin, and halpha-syn was found in the detergent-insoluble fraction. In high-expresser lines, the white matter tracts displayed intense astrogliosis, myelin pallor, and decreased neurofilament immunostaining. Accumulation of halpha-syn in oligodendrocytes also leads to prominent neurodegenerative changes in the neocortex with decreased dendritic density and to loss of dopaminergic fibers in the basal ganglia. The oligodendrocytic inclusions were composed of fibrils and accompanied by mitochondrial alterations and disruption of the myelin lamina in the axons. Together, these studies support the contention that accumulation of alpha-syn in oligodendrocytes promotes neurodegeneration and recapitulates several of the key functional and neuropathological features of MSA.
Shults
Clifford W
CW
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA.
Rockenstein
Edward
E
Crews
Leslie
L
Adame
Anthony
A
Mante
Michael
M
Larrea
Gabriel
G
Hashimoto
Makoto
M
Song
David
D
Iwatsubo
Takeshi
T
Tsuboi
Kyoko
K
Masliah
Eliezer
E
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
D051844:alpha-Synuclein