Genetic modifiers of the Drosophila blue cheese gene link defects in lysosomal transport with decreased life span and altered ubiquitinated-protein profiles.

Authors: Simonsen A; Cumming RC; Lindmo K; Galaviz V; Cheng S; Rusten TE; Finley KD
Year: 2007
Journal: Genetics
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.
Reference

Integration:

Created on Nov. 5, 2012, 6:23 p.m. and lastly updated on Nov. 7, 2012, 5:52 p.m.
Full text available
Integrated: True

Notes:

Mutation in several lysosomal trafficking genes results in significant decreased adult lifespan and several mutants exhibit changes in ubiquitinated protein profiles as young adults.

Autophagy primarily functions as an adaptive response to starvation or cellular stress by recycling non-essential cellular components for nutrition or by clearing old or damaged cytoplasmic material and organelles [Scott et al. 2004; Komatsu et al. 2005].

Alfy (autophagy-linked FYVE protein) is the conserved human bchs homolog [Simonsen et al. 2004].

Bchs/Alfy serve as scaffolding proteins, mediating a diverse series of protein and lipid interactions promoting the recruitment, organization, and transport of vesicles. Bchs/Alfy family aids in the removal of cytoplasmic ubiquitinated protein aggregates by promoting their autophagic clearance [Bojorkoy et al. 2005].

A bchs P-element insertion allele, bcsh was used for aging and starvation studies [Finley et al., 2003; FlyBase 2007].

Individual autophagy mutations act as strong homozygous lethal alleles, resulting in death at the late pupal or young adult stage of life.

atg8a might be partially redundant with atg8b. Atg8, also called LC3 (light chain of the microtubule-associated protein complex, MAP), undergoues C-terminal cleavage and covalent linkage to the lipid phosphatidylethnoalamine (PE) upon intercation with autophagic membranes [Kouno et al. 2005].

orange, ruby, garnet and carmine are the four subunits of the AP-3 protein complex. deep orange (dor, Vps18p, E3-ligase), carnation (Vps33, sec1 protein) and hook (colied-coil protein) act on the late endosomal pathway.

Simonsen, A., H. C. Birkeland, D. J. Gillooly, N. Mizushima, A. Kuma et al., 2004 Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J. Cell Sci. 117: 4239–4251.


Species: Fruit fly

Experiments: 2
  • TABLE 2 Adult life span profiles A. At 25°
  • TABLE 2 Adult life span profiles A. At 29°

  • Interventions:
  • hk mutation
  • car mutation
  • bchs mutation
  • cm mutation
  • lt mutation
  • g mutation
  • rb mutation
  • Atg8a mutation
  • dor mutation
  • ry mutation
  • car mutation

  • Edit study (Admin) | Add experiment to study (Admin) | Delete study

    Comment on This Data Unit