title: Cold temperature improves mobility and survival in Drosophila models of autosomal-dominant hereditary spastic paraplegia (AD-HSP).
abstract: Autosomal-dominant hereditary spastic paraplegia (AD-HSP) is a crippling neurodegenerative disease for which effective treatment or cure remains unknown. Victims experience progressive mobility loss due to degeneration of the longest axons in the spinal cord. Over half of AD-HSP cases arise from loss-of-function mutations in spastin, which encodes a microtubule-severing AAA ATPase. In Drosophila models of AD-HSP, larvae lacking Spastin exhibit abnormal motor neuron morphology and function, and most die as pupae. Adult survivors display impaired mobility, reminiscent of the human disease. Here, we show that rearing pupae or adults at reduced temperature (18°C), compared with the standard temperature of 24°C, improves the survival and mobility of adult spastin mutants but leaves wild-type flies unaffected. Flies expressing human spastin with pathogenic mutations are similarly rescued. Additionally, larval cooling partially rescues the larval synaptic phenotype. Cooling thus alleviates known spastin phenotypes for each developmental stage at which it is administered and, notably, is effective even in mature adults. We find further that cold treatment rescues larval synaptic defects in flies with mutations in Flower (a protein with no known relation to Spastin) and mobility defects in flies lacking Kat60-L1, another microtubule-severing protein enriched in the CNS. Together, these data support the hypothesis that the beneficial effects of cold extend beyond specific alleviation of Spastin dysfunction, to at least a subset of cellular and behavioral neuronal defects. Mild hypothermia, a common neuroprotective technique in clinical treatment of acute anoxia, might thus hold additional promise as a therapeutic approach for AD-HSP and, potentially, for other neurodegenerative diseases.
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Baxter
authors.affiliation: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Allard
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Crowl
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708, USA. ntangs@duke.edu.
authors.forename: Nina Tang
authors.initials: NT
authors.lastname: Sherwood
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D015220:Calcium Channels / Q000235:genetics; D003080:Cold Temperature; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D000074201:Katanin; D007814:Larva / Q000502:physiology; D008136:Longevity; D009043:Motor Activity; D009068:Movement; D009154:Mutation / Q000235:genetics; D011679:Pupa / Q000502:physiology; D015419:Spastic Paraplegia, Hereditary / Q000503:physiopathology*; D016019:Survival Analysis; D013569:Synapses / Q000473:pathology
chemical_list: D015220:Calcium Channels; D029721:Drosophila Proteins; C543900:fwe protein, Drosophila; D000251:Adenosine Triphosphatases; C501874:spas protein, Drosophila; C540495:Kat-60L1 protein, Drosophila; D000074201:Katanin
keywords: AD-HSP; Cold treatment; Drosophila disease model; Hereditary spastic paraplegia; Microtubule severing; Spastin; Therapeutic hypothermia