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Table 1 Pathogenic variants of CMA substrate protein in neurodegenerative disease

From: Chaperone-mediated autophagy: roles in neurodegeneration

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
  1. Note: \ (No reports are currently available); ↓ (Decrease); ↑ (Increase).