title: Genetic modifiers of the Drosophila blue cheese gene link defects in lysosomal transport with decreased life span and altered ubiquitinated-protein profiles.
abstract: Defects in lysosomal trafficking pathways lead to decreased cell viability and are associated with progressive disorders in humans. Previously we have found that loss-of-function (LOF) mutations in the Drosophila gene blue cheese (bchs) lead to reduced adult life span, increased neuronal death, and widespread CNS degeneration that is associated with the formation of ubiquitinated-protein aggregates. To identify potential genes that participate in the bchs functional pathway, we conducted a genetic modifier screen based on alterations of an eye phenotype that arises from high-level overexpression of Bchs. We found that mutations in select autophagic and endocytic trafficking genes, defects in cytoskeletal and motor proteins, as well as mutations in the SUMO and ubiquitin signaling pathways behave as modifiers of the Bchs gain-of-function (GOF) eye phenotype. Individual mutant alleles that produced viable adults were further examined for bchs-like phenotypes. Mutations in several lysosomal trafficking genes resulted in significantly decreased adult life spans and several mutants showed changes in ubiquitinated protein profiles as young adults. This work represents a novel approach to examine the role that lysosomal transport and function have on adult viability. The genes characterized in this study have direct human homologs, suggesting that similar defects in lysosomal transport may play a role in human health and age-related processes.
authors: Department of Biochemistry, Center for Cancer Biomedicine, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.
authors: Anne
authors: A
authors: Simonsen
authors: Robert C
authors: RC
authors: Cumming
authors: Karine
authors: K
authors: Lindmo
authors: Vanessa
authors: V
authors: Galaviz
authors: Susan
authors: S
authors: Cheng
authors: Tor Erik
authors: TE
authors: Rusten
authors: Kim D
authors: KD
authors: Finley
mesh_terms: D000818:Animals; D004251:DNA Transposable Elements; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007814:Larva; D008017:Life Expectancy; D018613:Microscopy, Confocal; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D021381:Protein Transport; D011679:Pupa; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D004251:DNA Transposable Elements; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; C472019:bchs protein, Drosophila