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.
Highlights
While lysosomes are responsible for the degradation and recycling of intra- and extracellular substrates (Saftig & Klumperman, 2009), they are increasingly recognized as regulators of cellular homeostasis and key players in nutrient sensing and transcriptionalAlabama at Birmingham School of Medicine, Birmingham, AL, USA Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, ON, Canada Department of Neurosurgery, Toronto Western Hospital, UHN, Toronto, ON, Canada University of Toronto, Toronto, ON, Canada GeneDx, Inc, Gaithersburg, MD, USA The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada a2021 The Authors
We focused on VPS41S285P, being the only variant significantly expressed in patient cells (Fig 3A), and included VPS41R662* as negative control, since Vacuolar protein sorting 41 (VPS41)–Homotypic fusion and Protein Sorting (HOPS) interaction requires the presence of the C-terminal RING domain absent in VPS41R662*
We find that lack of HOPS function causes increased dissociation of mechanistic target of rapamycin complex 1 (mTORC1) from lysosomes and the transfer of Transcription Factor E3 (TFE3) to the nucleus, resulting in continuously increased autophagy levels
Summary
While lysosomes are responsible for the degradation and recycling of intra- and extracellular substrates (Saftig & Klumperman, 2009), they are increasingly recognized as regulators of cellular homeostasis and key players in nutrient sensing and transcriptional. They were noted to have global developmental delay, poor muscle tone, and marked intentional tremor which further impaired their fine and gross motor skills Both brothers developed progressive spasticity of the lower limbs with some coarsening of the facial features more so in patient 2 with puffy eyelids, heavy eyebrows, and thick lips. Whole exome sequencing done on the brothers and their parents showed that both patients are compound heterozygote for variants in the VPS41 gene in trans; they carried a missense variant in the WD40 domain [Chr7(GRCh37)[(NM_014396.3:c.853T > C, NP_055211.2:pSer285Pro (S285P)(heterozygote, paternal); hereafter referred to as VPS41S285P] and a nonsense variant in the Clathrin Heavy Chain Repeat (CHCR) resulting in a truncated protein [c.1984C > T,NP_055211.2:pArg662Stop(R662*)(heterozygote, maternal); hereafter referred to as VPS41R662*] (Fig EV1C).
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