Resist-HD

Huntington’s disease (HD), the most frequent genetic neurodegenerative disease caused by unstable CAG repeat expansion, leads to selective degeneration of neurons, particularly spiny projection neurons (SPN) in the striatum. In consequence, the striatum is primarily affected in HD, resulting in a triad of cognitive, motor and psychiatric symptoms. Thus, understanding the mechanism underlying selective vulnerability of SPNs is key to the development of efficient treatment. While genetic factors appear as major drivers of the mechanism, environmental factors might also play significant role. This might be the case since several studies show substantial impact of environmental factors on behavioural symptoms of HD patients or mice. Particularly, enriched environment delayed disease onset and/or reduce symptom severity. Epigenetic & transcriptional reprogramming is implicated in vulnerability of HD SPNs and promotes their accelerated aging. We hypothesize that deciphering the interplay between environmental factors and epigenetic regulation in HD SPNs might foster translational research: first, supporting improvement of patients’ environmental conditions/life style, which can be rapidly implemented through public health policies; second, raising new therapeutic opportunities, notably leading to the identification of druggable pathways promoting the resistance of HD vulnerable neurons and/or counteracting their accelerated aging. Through manipulation of environmental conditions of HD mice and multi-omics analysis, the project aims to identify pathways that promote the resistance of SPNs in HD, and test promising targets in mice and cellular models, using viral-mediated approach or small molecules.