2. Academic Validation
  3. CHIP protects lysosomes from CLN4 mutant-induced membrane damages

CHIP protects lysosomes from CLN4 mutant-induced membrane damages

  • bioRxiv. 2025 Feb 19:2025.02.18.638932. doi: 10.1101/2025.02.18.638932.
Juhyung Lee 1,  Jizhong Zou 2,  Wan Nur Atiqah Binti Mazli 3,  Natalie Chin 1,  Michal Jarnik 4,  Layla Saidi 1,  Yue Xu 1,  John Replogle 5,  Michael Ward 5,  Juan Bonifacino 4,  Wei Zheng 6,  Ling Hao 3,  Yihong Ye 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 iPSC Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3 Department of Chemistry and Biochemistry, the University of Maryland, College Park, MD 20742, USA.
  • 4 Neurosciences and Cellular and Structural Biology Division, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
  • 6 Therapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20850, USA.
PMID: 40027688 DOI: 10.1101/2025.02.18.638932
Abstract

Understanding how cells mitigate lysosomal damage is critical for unraveling pathogenic mechanisms of lysosome-related diseases. Here we use organelle-specific proteomics in iPSC-derived neurons (i3Neuron) and an in vitro lysosome-damaging assay to demonstrate that lysosome damage, caused by the aggregation of Ceroid Lipofuscinosis Neuronal 4 (CLN4)-linked DNAJC5 mutants on lysosomal membranes, serves as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin Ligase CHIP as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP's lysosome protection function is transferrable, as ectopic CHIP improves lysosomal function in CLN4 i3Neurons, and effectively alleviates lipofuscin accumulation and neurodegeneration in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle damage guardian that preserves lysosome integrity, offering new insights into therapeutic development for CLN4 and Other lysosome-related neurodegenerative diseases.

Keywords

CHIP/STUB1; Ceroid Lipofuscinosis Neuronal/CLN4; DNAJC5/CSPα; Drosophila disease model; autophagy/microautophagy; lysosome membrane damage; lysosome storage disease/LSD; neurodegenerative disease; ubiquitin.

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