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

Abstract

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␣-synimmunoreactive 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.

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor

“…Although some nuclear staining has been observed in this model, distinct cytoplasmic inclusion-like structures have been consistently identified by confocal and electron microscopy (25,30). The mThy1-␣-syn mice were created and are maintained on a hybrid C57BL/6-DBA/2 background (25).…”

Animal models of multiple system atrophy

“…Based on the constitutive ectopic overexpression of aSyn in oligodendrocytes, a new experimental approach to mimic human MSA was developed [20][21][22]. Three oligodendroglia-specific promotors were used to induce overexpression of human wild type aSyn in transgenic mice, and the outcomes confirmed that aSyn accumulation in oligodendrocytes might trigger neurodegeneration.…”

“…The San Diego group around Shults and Masliah [22] approached genetic modeling of MSA through overexpression of human aSyn in the mouse brain under the myelin basic protein (MBP) promoter. Through developing several transgenic lines with different degrees of human aSyn overexpression in the mouse oligodendrocytes, they were the first to show that there is a clear cut correlation between the oligodendroglial aSyn dose the severity of the phenotype.…”

Microtubule Depolymerization Suppresses α-Synuclein Accumulation in a Mouse Model of Multiple System Atrophy

“…Three transgenic (Tg) mouse models in which human wild-type ␣-syn is overexpressed in CNS oligodendrocytes under the control of different promoters were generated. [13][14][15] Two of the three mouse lines showed that the accumulation of ␣-syn as GCIs leads to neuronal degeneration in the mouse CNS.…”