Neurodegeneration in a Transgenic Mouse Model of Multiple System Atrophy Is Associated with Altered Expression of Oligodendroglial-Derived Neurotrophic Factors

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. Neuronal degeneration is accompanied by primarily oligodendrocytic accumulation of alpha-synuclein (alpha syn) as opposed to the neuronal inclusions more commonly found in other alpha-synucleinopathies such as Parkinson's disease. It is unclear how alpha syn accumulation in oligodendrocytes may lead to the extensive neurodegeneration observed in MSA; we hypothesize that the altered expression of oligodendrocyte-derived neurotrophic factors by alpha syn may be involved. In this context, the expression of a number neurotrophic factors reportedly expressed by oligodendrocytes [glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor 1 (IGF-1), as well as basic fibroblast growth factor 2 (bFGF2), reportedly astrocyte derived] were examined in transgenic mouse models expressing human alpha syn (h alpha syn) under the control of either neuronal (PDGF beta or mThy1) or oligodendrocytic (MBP) promoters. Although protein levels of BDNF and IGF-1 were altered in all the alpha syn transgenic mice regardless of promoter type, a specific decrease in GDNF protein expression was observed in the MBP-h alpha syn transgenic mice. Intracerebroventricular infusion of GDNF improved behavioral deficits and ameliorated neurodegenerative pathology in the MBP-h alpha syn transgenic mice. Consistent with the studies in the MBP-h alpha syn transgenic mice, analysis of GDNF expression levels in human MSA samples demonstrated a decrease in the white frontal cortex and to a lesser degree in the cerebellum compared with controls. These results suggest a mechanism in which alpha syn expression in oligodendrocytes impacts on the trophic support provided by these cells for neurons, perhaps contributing to neurodegeneration.