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Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.

Reini E N van der Welle1, Rebekah Jobling2, Christian Burns3

  • 1Section Cell Biology, Center for Molecular Medicine, Institute of Biomembranes, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

EMBO Molecular Medicine
|April 14, 2021
PubMed
Summary

New mutations in the VPS41 gene cause neurodegeneration with ataxia and dystonia by disrupting lysosomal function and mTORC1 signaling. These findings link VPS41 (Vacuolar protein sorting 41) to neurodegenerative diseases.

Keywords:
AutophagyHOPS complexTFEB/TFE3lysosome-associated disordermTORC1

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Area of Science:

  • Cell Biology
  • Neuroscience
  • Genetics

Background:

  • Vacuolar protein sorting 41 (VPS41) is crucial for lysosomal fusion via the HOPS complex and for regulated secretion.
  • Dysfunctional VPS41 is implicated in various cellular processes, but its direct role in specific neurodegenerative conditions is not fully understood.

Purpose of the Study:

  • To investigate the cellular and molecular consequences of novel VPS41 mutations identified in patients with neurodegeneration.
  • To elucidate the impact of these VPS41 variants on HOPS complex function, lysosomal trafficking, and mTORC1 signaling pathways.

Main Methods:

  • Analysis of patient-derived fibroblasts and VPS41-depleted HeLa cells.
  • Investigation of lysosomal cargo delivery, mTORC1 signaling (including TFE3 localization), and autophagy.
  • Utilized a C. elegans model of Parkinson's disease to assess neuroprotection.

Main Results:

  • Identified compound heterozygous mutations in VPS41 (VPS41^S285P, VPS41^R662*, VPS41^c.1423-2A>G) in three patients with neurodegeneration, ataxia, and dystonia.
  • VPS41 mutants impaired HOPS complex formation, delayed lysosomal cargo delivery, and altered mTORC1/TFE3 signaling and autophagy.
  • VPS41 variants abolished neuroprotective effects in a C. elegans Parkinson's disease model.

Conclusions:

  • VPS41 variants disrupt HOPS function, leading to neurodegenerative disease by interfering with TFEB/TFE3-mediated mTORC1 signaling.
  • This study highlights the critical role of VPS41 in neuronal health and identifies novel pathogenic mechanisms in neurodegeneration.