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doi:10.1534/genetics.106.065011
A more recent version of this article appeared on June 1, 2007.
Originally published as Genetics Published Articles Ahead of Print on April 15, 2007.
REGULAR RESEARCH PAPERS |
Genetic Modifiers of the Drosophila Blue Cheese Gene Link Defects in Lysosomal Transport with Decreased Lifespan and Altered Ubiquitinated Protein Profiles
Anne Simonsen 1, Robert C. Cumming 1, Karine Lindmo 2, Vanessa Galaviz 1, Susan Cheng 1, Tor Erik Rusten 2 and Kim D. Finley 1*
1 The Salk Institute for Biological Studies
2 Institute for Cancer Research, The Norwegian Radium Hospital
* To whom correspondence should be addressed. E-mail: finley{at}salk.edu.
Submitted on February 22, 2007
Revised on March 16, 2007
Accepted on 11 April 2007
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 mutations (LOF) in the Drosophila gene blue cheese (bchs) leads to reduced adult lifespan, 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 lifespans 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 has on adult viability. The genes characterized in this study have direct human homologues, suggesting that similar defects in lysosomal transport may play a role in human health and age-related processes.
Key Words: adult viability, blue cheese, lysosomal transport, macroautophagy, ubiquitin
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