Fly model leads to new model for cellular mechanisms underlying diseases associated with disruption of Valosin-Containing Proteins

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

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

Johnson AE, Orr BO, Fetter RD, Moughamian AJ, Primeaux LA,
Geier EG, Yokoyama JS, Miller BL, Davis GW
 

From the 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. ... We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. ... 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.

DOI: 10.1038/s41467-020-20796-8
PMID: 33479240

Wondering what's IBMPFD? Answer: Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia.

New fly model: VCP mutation-dependent degeneration. Recent report.

Kim NC, Tresse E, Kolaitis RM, Molliex A, Thomas RE, Alami NH, Wang B, Joshi A, Smith RB, Ritson GP, Winborn BJ, Moore J, Lee JY, Yao TP, Pallanck L, Kundu M, Taylor JP. VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron. 2013 Apr 10;78(1):65-80. PMID: 23498974.

From the abstract: "Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget's disease, or a combination of these. The disease mechanism is unknown. We developed a Drosophila model of VCP mutation-dependent degeneration."

A related paper using human cells appears in the same issue of the journal. Bartolome et al. Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron. 2013 Apr 10;78(1):57-64. PMID: 23498975.