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Mol Brain. 2019 Mar 12;12(1):18. doi: 10.1186/s13041-019-0439-2.

Lysosomal dysfunction in proteinopathic neurodegenerative disorders: possible therapeutic roles of cAMP and zinc.

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Department of Neurology, University of Ulsan College of Medicine, Seoul, South Korea.
Neural Injury Lab, Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.
Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, South Korea.
Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.


A number of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, share intra- and/or extracellular deposition of protein aggregates as a common core pathology. While the species of accumulating proteins are distinct in each disease, an increasing body of evidence indicates that defects in the protein clearance system play a crucial role in the gradual accumulation of protein aggregates. Among protein degradation systems, the endosome-autophagosome-lysosome pathway (EALP) is the main degradation machinery, especially for large protein aggregates. Lysosomal dysfunction or defects in fusion with vesicles containing cargo are commonly observed abnormalities in proteinopathic neurodegenerative diseases. In this review, we discuss the available evidence for a mechanistic connection between components of the EALP-especially lysosomes-and neurodegenerative diseases. We also focus on lysosomal pH regulation and its significance in maintaining flux through the EALP. Finally, we suggest that raising cAMP and free zinc levels in brain cells may be beneficial in normalizing lysosomal pH and EALP flux.


EALP; Lysosome; MT3; Zinc; cAMP

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