Survival and mobility improve in HSP fruit flies
Fruit flies with Spastin (SPG4) mutations have had their survival rates improved and mobility restored by prolonged exposure to cool temperatures. These results were achieved with fruit flies at all stages of development from larvae through to adults.
Mild hypothermia may hold promise as a therapeutic approach for some types of HSP.
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 central nervous system.
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.
SOURCE: Dis Model Mech. 2014 Aug;7(8):1005-12. doi: 10.1242/dmm.013987. Epub 2014 Jun 6. © 2014. Published by The Company of Biologists Ltd. PMID: 24906373 [PubMed – in process]
Cold temperature improves mobility and survival in Drosophila models of autosomal-dominant hereditary spastic paraplegia (AD-HSP).
1Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
2Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
3Department of Biology, Duke University, Durham, NC 27708, USA.
4Department of Biology, Duke University, Durham, NC 27708, USA. [email protected].