A neuropathological hallmark in human HD and mouse models is the intracellular accumulation and aggregation of N-terminal Htt fragments, suggesting that aberrant Htt proteolysis and/or dysfunction in clearance of truncated Htt may underlie the neuropathology of HD.In a cell model of HD overexpressing Htt fragment 1-552 amino acid residues (Htt-552).We found that both macroautophagy and chaperon-mediated autophagy (CMA) were involved in degradation of Htt-552.Changing the levels of macroautopahgy and CMA effected the accumulation of Htt-552.Beclinl can interact with Htt-552 and redistributed from nucleus to the cytosol and knockdown of beclinl increased the accumulation of mutant Htt552, suggesting macroautophagy regulator beclinl plays a role in promoting degradation of Htt-552.Incubation of cell lysates containing expressed Htt-552 with isolated lysosomes demonstrated that Htt-552 bound to lysosomes and was transported into the lysosomal lumen for degradation.Expansion of potyQ tract in Htt-552 impaired its uptake and degradation by lysosomes.Mutation of putative KFERQ motif in wilt-type Htt-552 interfered with interactions between Htt-552 and Hsc70.These data suggest that CMA also plays a role in Htt degradation.Our studies indicate that both macroautophagy and CMA are involved in degradation of Htt and thus may represent an important therapeutic target.