New fly models with relevance to Multisystem Proteinopathy, ALS, and other valosin containig protein (VCP)-related diseases

"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 and novel treatment strategies."

Dis Model Mech. 2021 Jun 23:dmm.048603. doi: 10.1242/dmm.048603.

CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases.

Wall JM, Basu A, Zunica ERM, Dubuisson OS, Pergola K, Broussard JP, Kirwan JP, Axelrod CL, Johnson AE

Abstract

"Valosin containing protein (VCP) is a hexameric type II AAA ATPase required for several cellular processes including ER-associated degradation, organelle biogenesis, autophagy and membrane fusion. VCP contains three domains: a regulatory N-terminal domain and two ATPase domains (D1 and D2). Mutations in the N-terminal and D1 domains are associated with several degenerative diseases, including Multisystem Proteinopathy (MSP-1) and ALS. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. Having a deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. Over-expressing VCP patient mutations in Drosophila has been shown to mimic many pathologies observed in human patients. 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 and novel treatment strategies. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. We validate that these 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 laminopathies and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models we have generated in this study will be useful for studying the etiology of individual VCP patient mutations and for testing potential genetic and/or pharmacological therapies."

DOI: 10.1242/dmm.048603
PMID: 34160014

Review article: "Discovering signaling mechanisms governing metabolism and metabolic diseases with Drosophila"

Cell Metab. 2021 Jun 11:S1550-4131(21)00269-2. doi: 10.1016/j.cmet.2021.05.018.

Discovering signaling mechanisms governing metabolism and metabolic diseases with Drosophila.

Kim SK, Tsao DD, Suh GSB, Miguel-Aliaga I]

Abstract:

There has been rapid growth in the use of Drosophila and other invertebrate systems to dissect mechanisms governing metabolism. New assays and approaches to physiology have aligned with superlative genetic tools in fruit flies to provide a powerful platform for posing new questions, or dissecting classical problems in metabolism and disease genetics. In multiple examples, these discoveries exploit experimental advantages as-yet unavailable in mammalian systems. Here, we illustrate how fly studies have addressed long-standing questions in three broad areas-inter-organ signaling through hormonal or neural mechanisms governing metabolism, intestinal interoception and feeding, and the cellular and signaling basis of sexually dimorphic metabolism and physiology-and how these findings relate to human (patho)physiology. The imaginative application of integrative physiology and related approaches in flies to questions in metabolism is expanding, and will be an engine of discovery, revealing paradigmatic features of metabolism underlying human diseases and physiological equipoise in health.

Copyright © 2021 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2021.05.018
PMID: 34139200

Review article: Fly research & COVID-19

"Remarkably, 90% of the SARS-CoV-2 virus-host interacting proteins are conserved between Drosophila and humans."

 

Cell Biosci. 2021 Jun 13;11(1):110. doi: 10.1186/s13578-021-00621-5.

Drosophila, a powerful model to study virus-host interactions and pathogenicity in the fight against SARS-CoV-2

van de Leemput J, Han Z

Abstract:

"The COVID-19 pandemic is having a tremendous impact on humanity. Although COVID-19 vaccines are showing promising results, they are not 100% effective and resistant mutant SARS-CoV-2 strains are on the rise. To successfully fight against SARS-CoV-2 and prepare for future coronavirus outbreaks, it is essential to understand SARS-CoV-2 protein functions, their host interactions, and how these processes convey pathogenicity at host tissue, organ and systemic levels. In vitro models are valuable but lack the physiological context of a whole organism. Current animal models for SARS-CoV-2 research are exclusively mammals, with the intrinsic limitations of long reproduction times, few progeny, ethical concerns and high maintenance costs. These limitations make them unsuitable for rapid functional investigations of virus proteins as well as genetic and pharmacological screens. Remarkably, 90% of the SARS-CoV-2 virus-host interacting proteins are conserved between Drosophila and humans. As a well-established model system for studying human diseases, the fruit fly offers a highly complementary alternative to current mammalian models for SARS-CoV-2 research, from investigating virus protein function to developing targeted drugs. Herein, we review Drosophila's track record in studying human viruses and discuss the advantages and limitations of using fruit flies for SARS-CoV-2 research. We also review studies that already used Drosophila to investigate SARS-CoV-2 protein pathogenicity and their damaging effects in COVID-19 relevant tissues, as well as studies in which the fly was used as an efficient whole animal drug testing platform for targeted therapeutics against SARS-CoV-2 proteins or their host interacting pathways."

DOI: 10.1186/s13578-021-00621-5
PMCID: PMC8200282
PMID: 34120640