AI Discovery Lab -- Neurodegeneration & CMA-Autophagy
Most iPSC-derived HD models use high CAG repeat lines (>60) representing juvenile-onset HD. Adult-onset HD (36-44 CAG) phenotypes are poorly modeled in iPSC neurons due to epigenetic age reset during reprogramming.
While CMA and mitophagy are both impaired in neurodegeneration, their functional interaction in HD specifically remains almost entirely unexplored. Only PD models have been used to study this crosstalk.
While LAMP2A downregulation in HD is established, the precise mechanism remains debated. Splice variant dynamics, transcriptional regulation, and post-translational modifications of LAMP2A all need further investigation.
Nearly all CMA studies in HD focus on neurons. The role of astrocytic and microglial CMA in HD pathogenesis and potential non-cell-autonomous effects remains unexplored.