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Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
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CHIP protects lysosomes from CLN4 mutant-induced membrane damage.

Juhyung Lee1, Natalie Chin1, Jizhong Zou2

  • 1Laboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Nature Cell Biology
|August 26, 2025
PubMed
Summary
This summary is machine-generated.

Scientists discovered that CHIP-mediated microautophagy protects cells from lysosomal damage. This pathway, involving the ubiquitin ligase CHIP, offers a potential therapeutic strategy for neurodegenerative diseases like CLN4, reducing cell death and lipofuscin accumulation.

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Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • Lysosomal damage is central to neurodegenerative diseases.
  • CLN4-linked DNAJC5 mutations cause lysosomal abnormalities and neurodegeneration.
  • Cellular mechanisms for mitigating lysosomal damage are not fully understood.

Purpose of the Study:

  • To investigate the pathogenic mechanisms of CLN4-associated neurodegeneration.
  • To identify cellular pathways that protect against lysosomal damage.
  • To explore therapeutic targets for lysosome-related neurodegenerative diseases.

Main Methods:

  • Generation and characterization of induced pluripotent stem cell (iPSC)-derived neurons (i3Neuron) with CLN4 mutations.
  • In vitro membrane-damaging experiments to assess lysosomal damage.
  • Genome-wide CRISPR screens to identify regulators of microautophagy.
  • Testing CHIP's therapeutic potential in a Drosophila CLN4 disease model.

Main Results:

  • CLN4 mutant aggregates cause critical lysosomal damage in neurons.
  • A ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates in non-neuronal cells.
  • Genome-wide CRISPR screens identified CHIP as a key regulator of this protective microautophagy.
  • Ectopic CHIP expression improved lysosomal function and reduced pathology in CLN4 i3Neurons and a Drosophila model.

Conclusions:

  • CHIP-mediated microautophagy is a crucial mechanism for lysosome protection.
  • This pathway effectively counteracts CLN4-associated lysotoxicity and neurodegeneration.
  • CHIP represents a promising therapeutic target for lysosome-related neurodegenerative diseases.