Open AccessNeurodegenerative VPS41 variants inhibit HOPS function and mTORC1‐dependent TFEB/TFE3 regulation
Author(s) -
van der Welle Reini E N,
Jobling Rebekah,
Burns Christian,
Sanza Paolo,
van der Beek Jan A,
Fasano Alfonso,
Chen Lan,
Zwartkruis Fried J,
Zwakenberg Susan,
Griffin Edward F,
ten Brink Corlinda,
Veenendaal Tineke,
Liv Nalan,
van RavenswaaijArts Conny M A,
Lemmink Henny H,
Pfundt Rolph,
Blaser Susan,
Sepulveda Carolina,
Lozano Andres M,
Yoon Grace,
SantiagoSim Teresa,
Asensio Cedric S,
Caldwell Guy A,
Caldwell Kim A,
Chitayat David,
Klumperman Judith
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013258
Subject(s) - library science , gerontology , medicine , computer science
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 ( VPS41 S285P and VPS41 R662 * ; VPS41 c.1423‐2A>G and VPS41 R662 * ) 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, VPS41 S285P 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 VPS41 S285P / VPS41 R662 * 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.