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Research Paper|Volume 16, Issue 10|pp 9072—9105

Sensitivity of substrate translocation in chaperone-mediated autophagy to Alzheimer’s disease progression

Lei Yu1, Xinping Pang2, Lin Yang1, Kunpei Jin1, Wenbo Guo1, Yanyu Wei3, Chaoyang Pang1
  • 1College of Computer Science, Sichuan Normal University, Chengdu 610101, China
  • 2West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, China
  • 3National Key Laboratory of Science and Technology on Vacuum Electronics, School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
* Equal contribution and share first authorship
Received: November 9, 2023Accepted: April 15, 2024Published: May 23, 2024
https://doi.org/10.18632/aging.205856

Copyright: © 2024 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alzheimer’s disease (AD) is a progressive brain disorder marked by abnormal protein accumulation and resulting proteotoxicity. This study examines Chaperone-Mediated Autophagy (CMA), particularly substrate translocation into lysosomes, in AD. The study observes: (1) Increased substrate translocation activity into lysosomes, vital for CMA, aligns with AD progression, highlighted by gene upregulation and more efficient substrate delivery. (2) This CMA phase strongly correlates with AD’s clinical symptoms; more proteotoxicity links to worse dementia, underscoring the need for active degradation. (3) Proteins like GFAP and LAMP2A, when upregulated, almost certainly indicate AD risk, marking this process as a significant AD biomarker. Based on these observations, this study proposes the following hypothesis: As AD progresses, the aggregation of pathogenic proteins increases, the process of substrate entry into lysosomes via CMA becomes active. The genes associated with this process exhibit heightened sensitivity to AD. This conclusion stems from an analysis of over 10,000 genes and 363 patients using two AI methodologies. These methodologies were instrumental in identifying genes highly sensitive to AD and in mapping the molecular networks that respond to the disease, thereby highlighting the significance of this critical phase of CMA.