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CHIP protects lysosomes from CLN4 mutant-induced membrane damages
Juhyung Lee1, Jizhong Zou2, Wan Nur Atiqah Binti Mazli3
1Laboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Biorxiv : the Preprint Server for Biology
|March 3, 2025
Summary
Cellular defense against lysosomal damage is key for neurodegenerative diseases. CHIP-mediated microautophagy protects lysosomes from CLN4-linked damage, offering therapeutic potential for neurodegeneration.
Area of Science:
- Cellular Biology
- Neuroscience
- Molecular Biology
Background:
- Lysosomal damage is implicated in neurodegenerative diseases.
- Understanding cellular mechanisms for lysosome protection is crucial for disease pathogenesis.
Purpose of the Study:
- To investigate the role of lysosomal damage in Ceroid Lipofuscinosis Neuronal 4 (CLN4) disease.
- To identify cellular pathways that protect against CLN4-associated lysosomal damage and neurodegeneration.
Main Methods:
- Organelle-specific proteomics in induced pluripotent stem cell-derived neurons (i³Neurons).
- In vitro lysosome-damaging assays.
- Genome-wide CRISPR screens to identify key regulators.
- In vivo studies using a Drosophila CLN4 disease model.
Main Results:
- Lysosome damage from DNAJC5 mutant aggregation is central to CLN4 neurodegeneration.
- A ubiquitin-dependent microautophagy pathway, regulated by the ubiquitin ligase CHIP, protects against CLN4-associated lysotoxicity.
- CHIP's protective function is transferable and alleviates CLN4 disease phenotypes in neurons and Drosophila models.
Conclusions:
- CHIP-mediated microautophagy acts as a critical guardian of lysosomal integrity.
- This pathway offers a potential therapeutic target for CLN4 and other lysosome-related neurodegenerative diseases.
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