Wall 2021 Dis Model Mech
| Wall JM, Basu A, Zunica ERM, Dubuisson OS, Pergola K, Broussard JP, Kirwan JP, Axelrod CL, Johnson AE (2021) CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases. Dis Model Mech 14:dmm048603. |
Wall Jordan M, Basu Ankita, Zunica Elizabeth RM, Dubuisson Olga S, Pergola Kathryn, Broussard Joshua P, Kirwan John P, Axelrod Christopher L, Johnson Alyssa E (2021) Dis Model Mech
Abstract: Mutations in Valosin Containing Protein (VCP) are associated with several degenerative diseases, including multisystem proteinopathy (MSP-1) and amyotrophic lateral sclerosis. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. A deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. The power of a genetically tractable model organism coupled with well-established in vivo assays and a relatively short life cycle make Drosophila an attractive system to study VCP disease pathogenesis. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. Our models display many hallmarks of VCP-mediated degeneration, including progressive decline in mobility, protein aggregate accumulation and defects in lysosomal and mitochondrial function. We also made some novel and unexpected findings, including nuclear morphology defects and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models generated in this study will be useful for studying the etiology of individual VCP patient mutations and testing potential genetic and/or pharmacological therapies. • Keywords: Drosophila, IBMPFD, Lysosomes, MSP-1, Mitochondria, Ter94, VCP • Bioblast editor: Plangger M • O2k-Network Lab: US LA Baton Rouge Noland RC
Labels: MiParea: Respiration, nDNA;cell genetics
Pathology: Other
Organism: Drosophila Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET
Pathway: N, S, Gp, CIV, NS, ROX
HRR: Oxygraph-2k
2021-07
