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VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling

R.E.N. van der Welle, R. Jobling, C. Burns, P. Sanza, C. ten Brink, A. Fasano, L. Chen, F.J. Zwartkruis, S. Zwakenberg, E.F. Griffin, J. van der Beek, T. Veenendaal, N. Liv, S. Blaser, C. Sepulveda, A.M. Lozano, G. Yoon, C.S. Asensio, G.A. Caldwell, K.A. Caldwell, D. Chitayat, J. Klumperman
doi: https://doi.org/10.1101/2019.12.18.867333
R.E.N. van der Welle
1Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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R. Jobling
2Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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C. Burns
3Division of Natural Sciences and Mathematics, Department of Biological Sciences, University of Denver, Denver, CO, USA
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P. Sanza
1Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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C. ten Brink
1Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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A. Fasano
4Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada. Division of Neurology, University of Toronto, Toronto, Ontario, Canada
5Krembil Brain Institute, Toronto, Ontario, Canada
6Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada
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L. Chen
3Division of Natural Sciences and Mathematics, Department of Biological Sciences, University of Denver, Denver, CO, USA
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F.J. Zwartkruis
7Section Molecular Cancer research, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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S. Zwakenberg
7Section Molecular Cancer research, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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E.F. Griffin
8Department of Biological Sciences, The University of Alabama, 3307 Science and Engineering Complex, Tuscaloosa, AL, USA and Department of Neurology, University of Alabama at Birmingham School of Medicine, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Basic Research in the Biology of Aging, Birmingham, AL, USA
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J. van der Beek
1Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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T. Veenendaal
1Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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N. Liv
1Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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S. Blaser
9Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, ON, Canada
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C. Sepulveda
4Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada. Division of Neurology, University of Toronto, Toronto, Ontario, Canada
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A.M. Lozano
5Krembil Brain Institute, Toronto, Ontario, Canada
6Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada
10Department of Neurosurgery, Toronto Western Hospital, UHN, Toronto, Ontario, Canada. University of Toronto, Toronto, Ontario, Canada
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G. Yoon
2Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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C.S. Asensio
3Division of Natural Sciences and Mathematics, Department of Biological Sciences, University of Denver, Denver, CO, USA
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G.A. Caldwell
8Department of Biological Sciences, The University of Alabama, 3307 Science and Engineering Complex, Tuscaloosa, AL, USA and Department of Neurology, University of Alabama at Birmingham School of Medicine, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Basic Research in the Biology of Aging, Birmingham, AL, USA
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K.A. Caldwell
8Department of Biological Sciences, The University of Alabama, 3307 Science and Engineering Complex, Tuscaloosa, AL, USA and Department of Neurology, University of Alabama at Birmingham School of Medicine, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Basic Research in the Biology of Aging, Birmingham, AL, USA
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D. Chitayat
2Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
11The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada
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  • For correspondence: David.Chitayat@sinaihealthsystem.ca J.klumperman@umcutrecht.nl
J. Klumperman
1Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
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  • For correspondence: David.Chitayat@sinaihealthsystem.ca J.klumperman@umcutrecht.nl
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Abstract

The vacuolar protein sorting protein 41 (VPS41) is a neuroprotective protein in models of Parkinson’s disease (PD). As part of the HOPS (Homotypic fusion and Protein Sorting) complex, VPS41 regulates fusion of lysosomes with late endosomes and autophagosomes. Independent of HOPS, VPS41 regulates transport of newly synthesized lysosomal membrane proteins and secretory proteins. Here we report two brothers with compound heterozygous mutations in VPS41 (VPS41R662* and VPS41S285P), born to healthy and non-consanguineous parents. Both patients displayed transient retinal dystrophy, ataxia and dystonia, with brain MRI findings of cerebellar atrophy and a thin saber-shape corpus callosum. Patient-derived fibroblasts contained enzymatically active lysosomes that were poorly reached by endocytic cargo and failed to attract the mTORC1 complex. Consequently, transcription factor TFE3, a driver of autophagy and lysosomal genes, showed continuous nuclear localization which resulted in elevated LC3-II levels and an impaired response to nutrient starvation. CRISPR/CAS VPS41 HeLa knockout cells showed a similar phenotype that could be rescued by wildtype VPS41 but not by VPS41S285P or VPS41R662*. mTORC1 inhibition was also seen after knockout of HOPS subunits VPS11 or VPS18. Regulated neuropeptide secretion in PC12 VPS41 knockout cells was rescued by VPS41S285P expression, indicating that this HOPS-independent function was preserved. Co-expression of the VPS41S285P and VPS41R662* variants in a C. elegans model of PD abolished the protective effect of VPS41 against α-synuclein-induced neurodegeneration. We conclude that both disease-associated VPS41 variants specifically abrogate HOPS function, which leads to a delay in endocytic cargo delivery to lysosomes, mTORC1 inhibition and irresponsiveness to autophagic clues. Our studies signify a link between HOPS function and mTORC1 signaling and imply that HOPS function is required for the neuroprotective effect of VPS41 in PD.

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  • The authors have declared that no conflict of interest exists.

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VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling
R.E.N. van der Welle, R. Jobling, C. Burns, P. Sanza, C. ten Brink, A. Fasano, L. Chen, F.J. Zwartkruis, S. Zwakenberg, E.F. Griffin, J. van der Beek, T. Veenendaal, N. Liv, S. Blaser, C. Sepulveda, A.M. Lozano, G. Yoon, C.S. Asensio, G.A. Caldwell, K.A. Caldwell, D. Chitayat, J. Klumperman
bioRxiv 2019.12.18.867333; doi: https://doi.org/10.1101/2019.12.18.867333
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VPS41 recessive mutation causes ataxia and dystonia with retinal dystrophy and mental retardation by inhibiting HOPS function and mTORC1 signaling
R.E.N. van der Welle, R. Jobling, C. Burns, P. Sanza, C. ten Brink, A. Fasano, L. Chen, F.J. Zwartkruis, S. Zwakenberg, E.F. Griffin, J. van der Beek, T. Veenendaal, N. Liv, S. Blaser, C. Sepulveda, A.M. Lozano, G. Yoon, C.S. Asensio, G.A. Caldwell, K.A. Caldwell, D. Chitayat, J. Klumperman
bioRxiv 2019.12.18.867333; doi: https://doi.org/10.1101/2019.12.18.867333

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