Publications [#221052] of Nina T. Sherwood

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  1. Baxter SL, Allard DE, Crowl C, Sherwood NT, Cold temperature improves mobility and survival in Drosophila Models of Autosomal-Dominant Hereditary Spastic Paraplegia (AD-HSP)., Disease Models and Mechanisms (December, 2013) .
    (last updated on 2013/12/20)

    Author's Comments:
    Under revision for DMM.

    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 spastin mutants at reduced temperature (18˚C) compared to the standard temperature of 24˚C, improves survival, mobility, and synapse morphology. We confirm this using flies expressing human spastin with pathogenic mutations. The critical periods for cold-mediated rescue coincide with developmental time points during which spastin is required in neurons. Additionally, cold-treating adults significantly enhances mobility, suggesting that cooling alleviates neuronal dysfunction due to spastin mutations even in mature nervous systems. Although the mechanism(s) underlying this mitigation is unclear, cooling also improves mobility in mutants lacking Kat60-L1, a related microtubule severing protein. These data suggest that cold compensates for loss of microtubule severing, and that hypothermia may provide a unique therapeutic approach to AD-HSP.