Cold temperature improves mobility and survival in Drosophila models of autosomal-dominant hereditary spastic paraplegia (AD-HSP)

• Published in: Disease models & mechanisms Vol. 7; no. 8; pp. 1005 - 1012
• Main Authors: Baxter, Sally L, Allard, Denise E, Crowl, Christopher, Sherwood, Nina Tang
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.08.2014; The Company of Biologists Limited; The Company of Biologists
• Subjects: AD-HSP; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Animals; Animals, Genetically Modified; Calcium Channels - genetics; Cold; Cold Temperature; Cold treatment; Cooling; Disease; Disease Models, Animal; Drosophila disease model; Drosophila melanogaster - genetics; Drosophila melanogaster - physiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Genes; Genotype; Hereditary spastic paraplegia; Hypothermia; Hypotheses; Insects; Katanin; Larva - physiology; Longevity; Microtubule severing; Morphology; Motor Activity; Movement; Mutation; Mutation - genetics; Nervous system; Neurodegeneration; Neurons; Paralysis; Proteins; Pupa - physiology; Research Report; Spastic Paraplegia, Hereditary - physiopathology; Spasticity; Spastin; Survival Analysis; Synapses - pathology; Therapeutic hypothermia; Hereditary spastic paraplegia; Microtubule severing; Drosophila disease model; AD-HSP; Cold treatment; Therapeutic hypothermia; Spastin
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.013987

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.