Role of chaperone-mediated autophagy in Huntington's disease

Abstract

The accumulation of misfolded proteins is toxic in neurons and can lead to neurodegenerative diseases associated with aging. Huntington's disease (HD) is one of polyglutamine (polyQ) diseases caused by the expansion of the polyglutamine tract in the N-terminal huntingtin (Htt). Mutant Htt with expanded polyQ accumulates and forms aggregates in vulnerable neurons. Both ubiquitin proteasomal and autophagic pathways contribute to the degradation of mutant Htt. In this review, we focus on the involvement of chaperone-mediated autophagy (CMA), a selective form of autophagy in clearance of Htt. Selective catabolism in CMA is conferred by the presence of a KFERQ-like targeting motif in substrates, by which molecular chaperones recognize hydrophobic surfaces of misfolded substrates, and transfer them to the lysosomal membrane receptor, lamp2a. Substrates are taken into the lysosomes through lamp2a and are rapidly degraded by the lysosomal enzymes. This paper summarized recent evidence to elucidate that Htt is a potential substrate of CMA. We propose that manipulation of CMA could be a therapeutic strategy for HD. Plasmid construction, Transfection method of overexpression or knocking out proteins, Western blot, Co-immunoprecipitation, immunohistochemisty, PCR, DNA mutation, Cultivation of original generation cell and cell line, Mouse model, Segregation of organelles, Laser scanning confocal microscope. Western blot analysis certified the decreasing of Hsc/p70 or Lamp-2a results in the accumulation of Htt, vice versa. Lamp-2a and Hsc/p70 could be colocalized with Htt well. Htt could be banded to the menbrane of lysosome and uptaked by the lysosome. The present results suggest that CMA plays an important role in the degradation of Huntingtin protein (Htt) and protects cells expressing Htt from development of the disease.