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The Journal of Neuroscience, November 16, 2005, 25(46):10689-10699; doi:10.1523/JNEUROSCI.3527-05.2005

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Neurobiology of Disease
Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human -Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy

Clifford W. Shults,^1,2 Edward Rockenstein,¹ Leslie Crews,¹ Anthony Adame,¹ Michael Mante,¹ Gabriel Larrea,¹ Makoto Hashimoto,¹ David Song,^1,2 Takeshi Iwatsubo,³ Kyoko Tsuboi,^1,2 and Eliezer Masliah^1,4

¹Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, ²Veterans Affairs San Diego Healthcare System, San Diego, California 92161, ³Department of Neuropathology and Neuroscience, University of Tokyo, Tokyo 113-0033, Japan, and ⁴Department of Pathology, University of California, San Diego, La Jolla, California 92093-0820

Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of -synuclein (-syn) in oligodendrocytes. To better understand the mechanisms of neurodegeneration and the role of -syn accumulation in oligodendrocytes in the pathogenesis of MSA, we generated transgenic mouse lines expressing human (h) -syn under the control of the murine myelin basic protein promoter. Transgenic mice expressing high levels of h-syn displayed severe neurological alterations and died prematurely at 6 months of age. Furthermore, mice developed progressive accumulation of h-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) h-syn and ubiquitin, and h-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 h-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 -syn in oligodendrocytes promotes neurodegeneration and recapitulates several of the key functional and neuropathological features of MSA.

Key words: -synuclein; Lewy body disease; multiple system atrophy (MSA); transgenic; myelin basic protein (MBP) promoter; oxidative stress

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Received Oct 29, 2004; revised October 5, 2005; accepted October 5, 2005.

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