title: Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia.
abstract: The locomotor deficits in the group of diseases referred to as hereditary spastic paraplegia (HSP) reflect degeneration of upper motor neurons, but the mechanisms underlying this neurodegeneration are unknown. We established a Drosophila model for HSP, atlastin (atl), which encodes an ER fusion protein. Here, we show that neuronal atl loss causes degeneration of specific thoracic muscles that is preceded by other pathologies, including accumulation of aggregates containing polyubiquitin, increased generation of reactive oxygen species and activation of the JNK-Foxo stress response pathway. We show that inhibiting the Tor kinase, either genetically or by administering rapamycin, at least partially reversed many of these pathologies. atl loss from muscle also triggered muscle degeneration and rapamycin-sensitive locomotor deficits, as well as polyubiquitin aggregate accumulation. These results indicate that atl loss triggers muscle degeneration both cell autonomously and nonautonomously.
authors.affiliation: Department of BioSciences, Program in Biochemistry and Cell Biology, Rice University, Houston, TX 77005, USA.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of BioSciences, Program in Biochemistry and Cell Biology, Rice University, Houston, TX 77005, USA stern@rice.edu mcnew@rice.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Stern
authors.affiliation: Department of BioSciences, Program in Biochemistry and Cell Biology, Rice University, Houston, TX 77005, USA stern@rice.edu mcnew@rice.edu.
authors.forename: James A
authors.identifier: 0000-0001-8459-3664
authors.initials: JA
authors.lastname: McNew
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D008136:Longevity / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D025821:Polyubiquitin / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D015419:Spastic Paraplegia, Hereditary / Q000473:pathology* / Q000503:physiopathology
chemical_list: D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D025821:Polyubiquitin; D020123:Sirolimus
keywords: Atlastin; Degeneration; Membrane fusion; Polyubiquitin; Rapamycin