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<p>Understanding how cells mitigate lysosomal damage is critical for unravelling pathogenic mechanisms of lysosome-related diseases. Here we generate and characterize induced pluripotent stem cell (iPSC)-derived neurons (i<sup>3</sup>Neuron) bearing ceroid lipofuscinosis neuronal 4 (CLN4)-linked <i>DNAJC5</i> mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosomal damages caused by lysosome-associated CLN4 mutant aggregates, 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 carboxyl terminus of Hsc70-interacting protein (CHIP) as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP’s lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i<sup>3</sup>Neurons and effectively alleviates lipofuscin accumulation and cell death in a <i>Drosophila</i> CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, offering new insights into therapeutic development for lysosome-related neurodegenerative diseases.</p>

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CHIP protects lysosomes from CLN4 mutant-induced membrane damage

  • 期刊论文

  • 发表日期：

    2025年8月25日

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  • Juhyung Lee,
  • Natalie Chin,
  • Jizhong Zou,
  • Wan Nur Atiqah Binti Mazli,
  • Michal Jarnik,
  • Layla Saidi,
  • Yue Xu,
  • Eutteum Jeong,
  • Jessica Suh,
  • John Replogle,
  • Michael E. Ward,
  • Juan S. Bonifacino,
  • Wei Zheng,
  • Ling Hao,
  • Yihong Ye

摘要

Understanding how cells mitigate lysosomal damage is critical for unravelling pathogenic mechanisms of lysosome-related diseases. Here we generate and characterize induced pluripotent stem cell (iPSC)-derived neurons (i3Neuron) bearing ceroid lipofuscinosis neuronal 4 (CLN4)-linked DNAJC5 mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosomal damages caused by lysosome-associated CLN4 mutant aggregates, 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 carboxyl terminus of Hsc70-interacting protein (CHIP) as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP’s lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i3Neurons and effectively alleviates lipofuscin accumulation and cell death in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, offering new insights into therapeutic development for lysosome-related neurodegenerative diseases.