Neurodegenerative VPS41 Variants Inhibit HOPS Function and MTORC1-dependent TFEB/TFE3 Regulation

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2021 Apr 14

PMID 33851776

Citations 19

Authors

Reini E N van der Welle

Rebekah Jobling

Christian Burns

Paolo Sanza

Jan A van der Beek

Alfonso Fasano

Lan Chen

Fried J Zwartkruis

Susan Zwakenberg

Edward F Griffin

Corlinda Ten Brink

Tineke Veenendaal

Nalan Liv

Conny M A van Ravenswaaij-Arts

Henny H Lemmink

Rolph Pfundt

Susan Blaser

Carolina Sepulveda

Andres M Lozano

Grace Yoon

Teresa Santiago-Sim

Cedric S Asensio

Guy A Caldwell

Kim A Caldwell

David Chitayat

Judith Klumperman

Affiliations

Soon will be listed here.

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 (VPS41 and VPS41 ; VPS41 and VPS41 ) 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 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 /VPS41 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.

Citing Articles

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