Kinase activation in multiple system atrophy

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Multiple system atrophy (MSA) is an unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein accumulates preferentially in oligodendroglia rather than neurons. Accumulated alpha-synuclein, known as a glial cytoplasmic inclusion (GCI), is thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. We have developed novel rat and nonhuman primate (NHP) models of MSA by expressing alpha-synuclein in oligodendroglia using a novel glialoligodendrocyte-trophic adeno-associated virus (AAV) vector, Olig001. Histological analysis showed widespread expression of Oligo01- linked alpha-synuclein throughout the striatum and corpus callosum in rat brain with >90% localized to oligodendroglia and little to no expression in neurons or astrocytes. The model also displays demyelination in the white matter tracts of the corpus callosum and striatum, similar to what is observed in patient brain. Analysis of GCIs from the model animals revealed that they contain disease-specific phosphorylations at Tyr39 and Ser129 that are identical to the modifications of alpha-synuclein seen in neurons of Parkinson's Disease (PD) patients. The unexpected observation of these modifications in MSA model brain were also found in MSA patient brain (see Innovation) further validated the suitability of this rat model for the study of disease mechanism in MSA. While both MSA and PD are synucleinopathies, it has long been thought that the origin of pathology for these two diseases were distinct. The observation of disease-specific chemical modifications in MSA that are identical to what is observed in PD suggests a closer mechanistic linkage between these disparate diseases. In particular, since activation of the Abelson tyrosine kinase c-Abl is a key disease-initiating event in PD that results in phosphorylation at Tyr39, it is possible that c-Abl plays a similar role in MSA and that chemical inhibition of c- Abl could be disease-modifying in MSA. This suggests that treatment for MSA may be benefited by an orally bioavailable, brain-penetrant c-Abl kinase inhibitor, just as we've shown for Parkinson's Disease. Using this newly defined model of MSA, we propose to determine whether MSA has the same critical dependency on c-Abl activation that has been found in PD, paving the way for disease modifying therapy.