Chaperone-mediated autophagy: roles in neurodegeneration

Table 1 Pathogenic variants of CMA substrate protein in neurodegenerative disease

CMA substrate/binding Protein	Physiology function	Pathogenic mutant variants	Molecular mechanism	Effects on CMA activity	Disease
Ubiquitin C-terminal hydrolase L1 (UCH-L1) [52, 58]	Neuronal deubiquitinating enzyme	I93M	Abnormal binding to LAMP2A to block degradation by CMA substrates	↓	PD
α-synuclein [51, 55]	Function is not well understood	A30P, A53T	Abnormally high affinity binding to LAMP2A to prevent the translocation across the lysosomal membrane	↓	PD
Leucine-rich repeat kinase 2 (LRRK2) [59, 60]	Involved in mitogen-activated protein kinase, protein translation control, programmed cell death, and activity in cytoskeleton dynamics	G2019S	Interference with the organization of the CMA translocation complex and cause defective CMA	↓	PD
Tau [53, 57]	Stabilization of microtubules	FTDP-17 mutation (TauRDΔK280)	Oligomerization at the surface of lysosomes to disrupt the membrane integrity and blockage of normal CMA function	↓	AD
Regulator of calcineurin 1 (RCAN1) [61]	A mediator of stress- and Aβ-induced neuronal death	\	Mechanistic effects on lysosome unclear	↓	AD
Huntingtin [7, 45, 56]	Unclear and essential for development	Expansion of polyglutamine	Increased clearance via regulation of LAMP2A and lys-Hsc70	↑(early stages); ↓(late stages)	HD

ISSN: 2047-9158