2. Academic Validation
  3. Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation

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

  • EMBO Mol Med. 2021 May 7;13(5):e13258. doi: 10.15252/emmm.202013258.
Reini E N van der Welle 1,  Rebekah Jobling 2,  Christian Burns 3,  Paolo Sanza 1,  Jan A van der Beek 1,  Alfonso Fasano 4 5 6 7,  Lan Chen 3,  Fried J Zwartkruis 8,  Susan Zwakenberg 8,  Edward F Griffin 9 10,  Corlinda Ten Brink 1,  Tineke Veenendaal 1,  Nalan Liv 1,  Conny M A van Ravenswaaij-Arts 11,  Henny H Lemmink 11,  Rolph Pfundt 12,  Susan Blaser 13,  Carolina Sepulveda 4 5,  Andres M Lozano 6 7 14 15,  Grace Yoon 2,  Teresa Santiago-Sim 16,  Cedric S Asensio 3,  Guy A Caldwell 9 10,  Kim A Caldwell 9 10,  David Chitayat 2 17,  Judith Klumperman 1
Affiliations

Affiliations

  • 1 Section Cell Biology, Center for Molecular Medicine, Institute of Biomembranes, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 2 Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • 3 Department of Biological Sciences, Division of Natural Sciences and Mathematics, University of Denver, Denver, CO, USA.
  • 4 Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, ON, Canada.
  • 5 Division of Neurology, University of Toronto, Toronto, ON, Canada.
  • 6 Krembil Brain Institute, Toronto, ON, Canada.
  • 7 Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada.
  • 8 Section Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 9 Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA.
  • 10 Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Basic Research in the Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
  • 11 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • 12 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 13 Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, ON, Canada.
  • 14 Department of Neurosurgery, Toronto Western Hospital, UHN, Toronto, ON, Canada.
  • 15 University of Toronto, Toronto, ON, Canada.
  • 16 GeneDx, Inc, Gaithersburg, MD, USA.
  • 17 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada.
PMID: 33851776 DOI: 10.15252/emmm.202013258
Abstract

Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41S285P and VPS41R662* ; VPS41c.1423-2A>G and VPS41R662* ) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41S285P enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41S285P /VPS41R662* abolished the neuroprotective function of VPS41 against α-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.

Keywords

Autophagy; HOPS complex; TFEB/TFE3; lysosome-associated disorder; mTORC1.

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