Role of chaperone-mediated autophagy in ageing and neurodegeneration

Abstract

Depending on the mechanism and molecular players involved in the targeting of a substrate to the lysosome, autophagy can be divided in three different subtypes: Macroautophagy, Microautophagy and Chaperone-Mediated Autophagy (CMA). In contrast to other forms of autophagy, in CMA, soluble cytosolic proteins can be targeted selectively for degradation in lysosomes. Selectivity in CMA is conferred by the presence of a pentapeptide motif in the amino acid sequence of the substrate proteins, biochemically related to KFERQ, that is recognized by the cytosolic chaperone Hsc70, which results in the targeting of substrates to the lysosome. Once at the lysosomal surface, the substrate-chaperone complex binds to the membrane, and, after unfolding the substrate, is translocated into the lumen by LAMP2A, that acts as the resident a CMA "receptor". CMA has been implicated both in the elimination of parts of the proteome damaged by stressors, as well as, in the selective turnover of substrates directly related with several proteinophaties, most notably in neurodegenerative diseases. In this chapter we will focus on the role of CMA in age-related neurodegeneration and how CMA often becomes the target of the toxic effect of neurodegeneration-related aberrant substrates. The mulfactorial nature of the CMA role in neurodegenerative disorders makes the careful analyses of the evidences gathered thus far instrumental for the understanding of CMA in the context of these diseases.