CHOLESTEROL DYSFUNCTION IN HUNTINGTON¿S DISEASE: WORKING TOWARD A THERAPEUTICAL APPROACH

Cholesterol is a multifaceted membrane component particularly enriched in neurons and it is essential for brain function. In the adult brain, cholesterol is locally produced by astrocytes and transferred to neurons. Disruption of brain cholesterol pathways has been linked to several neurological diseases, including Huntington’s disease (HD). HD is a genetic, neurodegenerative disorder caused by a CAG expansion in the gene encoding the huntingtin protein leading to behavioral deficits, synaptic dysfunction, and neuronal loss. Brain cholesterol biosynthesis and content are reduced in several HD models due to reduced activity of SREBP2, the transcription factor that regulates cholesterol synthesis. Abnormalities in brain cholesterol homeostasis are also detectable in HD patients since 24-hydroxy-cholesterol, a cholesterol catabolite that is brain specific and able to cross the blood-brain barrier, is progressively reduced in their plasma. Of note, the delivery of cholesterol to the HD brain via systemic administration of brain-permeable polymeric nanoparticles (g7-NPs-chol_1.0) or directly into the striatum using osmotic-minipumps rescued key features of the disease. Here, to transform these results into a testable therapeutic strategy for humans, we characterized in vivo second generation g7-NPs (g7-NPs-chol_2.0), with an enhanced cholesterol loading capacity compared to g7-NPs-chol_1.0, to deliver the proper amount of cholesterol to the brain without side effects. Furthermore, we showed that multiple cycles of g7-NPs-chol_2.0 treatments lead to complete and long-term behavioral amelioration. Finally, to test the impact of forced SREBP2 expression within HD brain, we used AAV2/5 to deliver SREBP2 in astrocytes. We found that exogenous SREBP2 stimulates the transcription of cholesterol biosynthesis genes resulting in restoration of synaptic transmission and rescue of behavioral deficits. These results suggested that providing exogenous cholesterol or stimulating its biosynthesis in HD brain has a positive effect on behavioral decline and HD- related phenotypes, highlighting the translational potential of cholesterol-based strategies for this tremendous disease.