Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP.

Huntington's disease (HD) is an inherited neurodegenerative disorder that affects one in every 10,000 Americans. To date, there is no effective treatment for HD, in part because the pathogenic mechanism driving the disease is not fully understood. The dysfunction of astrocytes is known to contribute to the pathogenesis of HD. One important role of astrocytes is to synthesize and release brain-derived neurotrophic factor (BDNF), which is vital for neuronal survival, development, and function. We found that mutant huntingtin protein (mHtt) at the endogenous level decreases BDNF secretion from astrocytes by disrupting the conversion of GTP-Rab3a into GDP-Rab3a and that overexpressing Rab3a can rescue this deficient BDNF release and early neuropathology in HD knock-in mouse brain. Our study suggests that astrocytic Rab3a is a potential therapeutic target for HD treatment.