Doctor of Philosophy (PhD)
Multisystem Proteinopathy-1 (MSP-1) is a rare, autosomal dominant, degenerative disease resulting from single amino acid mis-sense mutations in the AAA+ ATPase, Valosin containing protein (VCP). Patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. To investigate the pathology of VCP- related disease, we engineered CRISPR knock-in Drosophila models for nine MSP-1 associated VCP mutations. These mutant animals mimic human MSP-1 disease phenotypes, including progressive mobility decline and accumulation of protein aggregates, making them excellent models to study the pathology of VCP associated mutations and test potential treatment strategies. At the cellular level, we observed a severe disruption of a tubular lysosomal (TL) network in the muscles, suggesting that TL defects may be a causative factor in MSP-1 pathology. In previous work, we demonstrated that TLs are a highly digestive pool of lysosomes and confer pro-health and/or pro-longevity benefits. As such, we reasoned that restoring the TL network in muscles might rescue the defects caused by VCP mutations. The integrity of the TL network is largely dependent on the VCP co-factor, SVIP, which directly recruits VCP to the lysosomal membranes. When SVIP is over-expressed in the muscles, TL density increases above basal levels and extends lifespan. Thus, to test this strategy, we over-expressed SVIP in the muscles of two VCP mutants (R152H and R152C) and examined effects on cellular and organismal health. Intriguingly, SVIP over-expression was sufficient to recruit the entire population of mutant VCP to lysosomes and restore the TL network. This was accompanied by reduced protein aggregation, improved mobility, and increased lifespan. Taken together, these results demonstrate that SVIP over- expression has the ability to rescue VCP disease pathology and can be a promising therapeutic target in treating MSP-1 and potentially other degenerative diseases that display similar phenotypic defects.
Basu, Ankita, "SVIP Dependent Tubular Lysosomal Restoration: A New Direction in VCP Diseases" (2023). LSU Doctoral Dissertations. 6105.
Available for download on Thursday, April 02, 2026