Aberrant Interaction between Parkinson Disease-associated Mutant UCH-L1 and the Lysosomal Receptor for Chaperone-mediated Autophagy
Open accessAbstract
Parkinson disease (PD) is the most common neurodegenerative movement disorder. An increase in the amount of alpha-synuclein protein could constitute a cause of PD. Alpha-synuclein is degraded at least partly by chaperone-mediated autophagy (CMA). The I93M mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) is associated with familial PD. However, the relationship between alpha-synuclein and UCH-L1 in the pathogenesis of PD has remained largely unclear. In this study, we found that UCH-L1 physically interacts with LAMP-2A, the lysosomal receptor for CMA, and Hsc70 and Hsp90, which can function as components of the CMA pathway. These interactions were abnormally enhanced by the I93M mutation and were independent of the monoubiquitin binding of UCH-L1. In a cell-free system, UCH-L1 directly interacted with the cytosolic region of LAMP-2A. Expression of I93M UCH-L1 in cells induced the CMA inhibition-associated increase in the amount of alpha-synuclein. Our findings may provide novel insights into the molecular links between alpha-synuclein and UCH-L1 and suggest that aberrant interaction of mutant UCH-L1 with CMA machinery, at least partly, underlies the pathogenesis of PD associated with I93M UCH-L1.
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This led to the identification of some of the earliest disease-associated genes, including APP, PS1 and PS2 in AD, SNCA and LRRK2 in PD and MAPT and GRN in FTD.
“This subsequently led to the identification of some of the earliest disease-associated genes, including APP, PS1 and PS2 in AD, SNCA and LRRK2 in PD and MAPT and GRN in FTD.79–87”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [82]
The paper’s introductory passage reports that mutations and copy-number increases in the α-synuclein gene (SNCA) are linked to familial Parkinson disease. It does not address the listed AD or FTD genes, LRRK2, or the claim that these were among the earliest disease-associated genes identified. (LLM, conf=0.85)
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- Authors
- Kabuta, T., Furuta, A., Aoki, S., Furuta, K., & Wada, K.
- Affiliations
- National Center of Neurology and Psychiatry (JP)
- National Cancer Center Hospital (JP)
- Corresponding author
- Kabuta, Tomohiro
- Wada, Keiji
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 283
- Issue
- 35
- Pages
- 23731-23738
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3259779
- OpenAlex
- W2005884107
- Cited by
- 227
- References
- 2
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 12 · 2023: 9 · 2022: 12 · 2021: 11 · 2020: 15 · 2019: 5 · 2018: 15 · 2017: 9 · 2016: 15 · 2015: 19 · 2014: 11 · 2013: 14 · 2012: 13
- FWCI
- 11.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Biomedical Innovation
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Parkinson's disease, UCHL1, chaperone-mediated autophagy, LAMP2A, alpha-synuclein, Hsc70, HSP90, protein-protein interaction, familial Parkinson's disease, protein degradation
- MeSH terms
- Animals, Autophagy, Chlorocebus aethiops, Humans, Mutation, Parkinson Disease, Protein Structure, Tertiary, HSP90 Heat-Shock Proteins, COS Cells, NIH 3T3 Cells, Ubiquitin Thiolesterase, HSC70 Heat-Shock Proteins, Mice, alpha-Synuclein, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 2
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