ArticleProceedings of the National Academy of Sciences of the United States of America2009
Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 83 citations in OpenAlex.
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- Non-muscle MYH10/myosin IIB recruits ESCRT-III to participate in autophagosome closure to maintain neuronal homeostasis.Autophagy · 2023Article
- The enhanced association between mutant CHMP2B and spastin is a novel pathological link between frontotemporal dementia and hereditary spastic paraplegias.Acta neuropathologica communications · 2022Article
- Drone honey bees are disproportionately sensitive to abiotic stressors despite expressing high levels of stress response proteins.Communications biology · 2022Article
- Clinical Correlation and Role of Cyclin D1 Expression in Glioblastoma Patients: A Study From North India.Cureus · 2022Article
- CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1.The Journal of cell biology · 2022Article
- Trade-offs between sperm viability and immune protein expression in honey bee queens (Apis mellifera).Communications biology · 2021Article
- Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons.Journal of Parkinson's disease · 2021Article
- Neuroprotective activity of ursodeoxycholic acid in CHMP2BNeurobiology of disease · 2020Article
- Retrovirus reactivation in CHMP2BIntron5 models of frontotemporal dementia.Human molecular genetics · 2020Article
- Ik2/TBK1 and Hook/Dynein, an adaptor complex for early endosome transport, are genetic modifiers of FTD-associated mutant CHMP2B toxicity in Drosophila.Scientific reports · 2020Article
- Expression of a human variant of CHMP2B linked to neurodegeneration in Drosophila external sensory organs leads to cell fate transformations associated with increased Notch activity.Developmental neurobiology · 2020Article
- Expression of mutant CHMP2B linked to neurodegeneration in humans disrupts circadian rhythms inFASEB bioAdvances · 2019Article
- Elimination of oncogenic cells that regulate epithelial homeostasis in Drosophila.Development, growth & differentiation · 2019Review
- The Manduca sexta serpinome: Analysis of serpin genes and proteins in the tobacco hornworm.Insect biochemistry and molecular biology · 2018Article
- Molecular Genetics of Frontotemporal Dementia Elucidated byInternational journal of molecular sciences · 2018Review
- The pro-apoptotic JNK scaffold POSH/SH3RF1 mediates CHMP2BIntron5-associated toxicity in animal models of frontotemporal dementia.Human molecular genetics · 2018Article
- WIPI1, BAG1, and PEX3 Autophagy-Related Genes Are Relevant Melanoma Markers.Oxidative medicine and cellular longevity · 2018Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Frontotemporal dementia (FTD) is the most common form of dementia before 60 years of age. Rare pathogenic mutations in CHMP2B, which encodes a component of the endosomal sorting complex required for transport (ESCRT-III), are associated with FTD linked to chromosome 3 (FTD3). Animal models of FTD3 have not yet been reported, and what signaling pathways are misregulated by mutant CHMP2B in vivo is unknown. Here we report the establishment of a Drosophila model of FTD3 and show the genetic interactions between mutant CHMP2B and other components of ESCRT. Through an unbiased genome-wide screen, we identified 29 modifier loci and found that serpin5 (Spn5), a largely uncharacterized serine protease inhibitor, suppresses the melanization phenotype induced by mutant CHMP2B in the fly eye. We also found that Spn5 is a negative regulator of the Toll pathway and functions extracellularly, likely by blocking the proteolytic activation of Spaetzle, the Toll receptor ligand. Moreover, Spn5 inhibited activation of the Toll pathway by mutant CHMP2B. Our findings identify Spn5 as a regulator of the Toll pathway and CHMP2B toxicity and show that the Toll pathway is a major signaling pathway misregulated by mutant CHMP2B in vivo. This fly model will be useful to further dissect genetic pathways that are potentially relevant to the pathogenesis and treatment of FTD.
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