Connection between astrocytes, cholesterol and synaptic dysfunction in Huntington’s disease

Huntington's disease (HD) is a genetic, neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding the huntingtin (HTT) protein. Clinically, HD is characterized by motor, cognitive, and psychiatric disturbances and is associated with neuronal and synaptic dysfunction and progressive loss of striatal and cortical neurons. Several molecular and cellular dysfunctions have been identified in HD, and one affected pathway implicates brain cholesterol. Brain cholesterol biosynthesis is reduced across different HD animal models suggesting that newly cholesterol is less available to neurons. This might be detrimental for neuronal cells, especially given that locally synthesized cholesterol is implicated in neurite outgrowth, synapses formation, maintenance and activity, and optimal neurotransmitter release. Here I will present our recent findings suggesting that astrocytes carrying the HD mutation are the major responsible of cholesterol dysfunction in HD as they contribute to supply less cholesterol to the surrounding neurons. Finally, I will show our in vivo studies demonstrating that delivery of exogenous cholesterol supplementation in the brain of HD mice rescues molecular, functional and behavioral aspects of the disease.