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

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.