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Targeting chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapeutic potential

Acta Pharmacologica Sinica volume 46, pages 816–828 (2025)Cite this article

Abstract

The pathological hallmarks of various neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease prominently feature the accumulation of misfolded proteins and neuroinflammation. Chaperone-mediated autophagy (CMA) has emerged as a distinct autophagic process that coordinates the lysosomal degradation of specific proteins bearing the pentapeptide motif Lys-Phe-Glu-Arg-Gln (KFERQ), a recognition target for the cytosolic chaperone HSC70. Beyond its role in protein quality control, recent research underscores the intimate interplay between CMA and immune regulation in neurodegeneration. In this review, we illuminate the molecular mechanisms and regulatory pathways governing CMA. We further discuss the potential roles of CMA in maintaining neuronal proteostasis and modulating neuroinflammation mediated by glial cells. Finally, we summarize the recent advancements in CMA modulators, emphasizing the significance of activating CMA for the therapeutic intervention in neurodegenerative diseases.

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Fig. 1: Schematic diagram of three main autophagy pathways.
Fig. 2: Schematic diagram of steps and regulation of chaperone-mediated autophagy (CMA).
Fig. 3: Schematic diagram of KFERQ-like motif.
Fig. 4: Association between CMA and inflammatory signaling pathways.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 32400789 and 32070970), the Natural Science Foundation of Jiangsu Province (grants BK20240436), the Suzhou Science and Technology Development Plan (SZM2023006 and SKYD2023179), and the Gusu Key Health Talent Program of Suzhou (GSWS2022122).

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  1. Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China

    Jin Wu, Wan Xu, Ying Su & Jing-jing Ma

  2. Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Guang-hui Wang

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  1. Jin Wu
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  3. Ying Su
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Wu, J., Xu, W., Su, Y. et al. Targeting chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapeutic potential. Acta Pharmacol Sin 46, 816–828 (2025). https://doi.org/10.1038/s41401-024-01416-3

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