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Originally published as Genetics Published Articles Ahead of Print on April 15, 2007.

Genetics, Vol. 176, 1283-1297, June 2007, Copyright © 2007
doi:10.1534/genetics.106.065011

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Genetic Modifiers of the Drosophila Blue Cheese Gene Link Defects in Lysosomal Transport With Decreased Life Span and Altered Ubiquitinated-Protein Profiles

Anne Simonsen*,{dagger}, Robert C. Cumming*, Karine Lindmo{dagger}, Vanessa Galaviz*, Susan Cheng*, Tor Erik Rusten{dagger} and Kim D. Finley*,1

* Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037 and {dagger} Department of Biochemistry, Center for Cancer Biomedicine, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway

1 Corresponding author: Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, California 92037.
E-mail: finley{at}salk.edu

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.






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Copyright © 2007 by the Genetics Society of America.