Cold temperature improves mobility and survival in drosophila models of Autosomal-Dominant Hereditary Spastic Paraplegia (AD-HSP)

Abstract

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 motoneuron 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 to 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 mutants of 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 that cold's beneficial effects 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, may thus hold additional promise as a therapeutic approach for AD-HSP, and potentially, other neurodegenerative diseases.