SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan

Alyssa E Johnson; Brian O Orr; Richard D Fetter; Armen J Moughamian; Logan A Primeaux; Ethan G Geier; Jennifer S Yokoyama; Bruce L Miller; Graeme W Davis

doi:10.1038/s41467-020-20796-8

SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan

Nat Commun. 2021 Jan 21;12(1):513. doi: 10.1038/s41467-020-20796-8.

Authors

Alyssa E Johnson^{1

2}, Brian O Orr¹, Richard D Fetter¹, Armen J Moughamian^{1

3}, Logan A Primeaux², Ethan G Geier^{2

4}, Jennifer S Yokoyama⁴, Bruce L Miller⁴, Graeme W Davis⁵

Affiliations

¹ Department of Biochemistry and Biophysics, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, 94158, USA.
² Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA.
³ Department of Neurology, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁴ Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, 94158, USA.
⁵ Department of Biochemistry and Biophysics, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, 94158, USA. Graeme.davis@ucsf.edu.

Abstract

Missense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson's disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal-lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism
Animals
Animals, Genetically Modified
Disease Models, Animal
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Drosophila melanogaster / genetics
Drosophila melanogaster / metabolism
Frontotemporal Dementia / genetics
Frontotemporal Dementia / metabolism
Humans
Longevity / genetics*
Lysosomes / metabolism*
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Muscular Dystrophies, Limb-Girdle / genetics
Muscular Dystrophies, Limb-Girdle / metabolism
Mutation*
Myositis, Inclusion Body / genetics
Myositis, Inclusion Body / metabolism
Neurodegenerative Diseases / genetics*
Neurodegenerative Diseases / metabolism
Osteitis Deformans / genetics
Osteitis Deformans / metabolism
Phosphate-Binding Proteins / genetics*
Phosphate-Binding Proteins / metabolism
Protein Binding
Valosin Containing Protein / genetics*
Valosin Containing Protein / metabolism

Substances

Drosophila Proteins
Membrane Proteins
Phosphate-Binding Proteins
SVIP protein, human
Valosin Containing Protein

Supplementary concepts

Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding