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Focused Cerebellar Laser Light Induced Hyperthermia Improves Symptoms and Pathology of Polyglutamine Disease SCA1 in a Mouse Model

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Abstract

Spinocerebellar ataxia 1 (SCA1) results from pathologic glutamine expansion in the ataxin-1 protein (ATXN1). This misfolded ATXN1 causes severe Purkinje cell (PC) loss and cerebellar ataxia in both humans and mice with the SCA1 disease. The molecular chaperone heat-shock proteins (HSPs) are known to modulate polyglutamine protein aggregation and are neuroprotective. Since HSPs are induced under stress, we explored the effects of focused laser light induced hyperthermia (HT) on HSP-mediated protection against ATXN1 toxicity. We first tested the effects of HT in a cell culture model and found that HT induced Hsp70 and increased its localization to nuclear inclusions in HeLa cells expressing GFP-ATXN1[82Q]. HT treatment decreased ATXN1 aggregation by making GFP-ATXN1[82Q] inclusions smaller and more numerous compared to non-treated cells. Further, we tested our HT approach in vivo using a transgenic (Tg) mouse model of SCA1. We found that our laser method increased cerebellar temperature from 38 to 40 °C without causing any neuronal damage or inflammatory response. Interestingly, mild cerebellar HT stimulated the production of Hsp70 to a significant level. Furthermore, multiple exposure of focused cerebellar laser light induced HT to heterozygous SCA1 transgenic (Tg) mice significantly suppressed the SCA1 phenotype as compared to sham-treated control animals. Moreover, in treated SCA1 Tg mice, the levels of PC calcium signaling/buffering protein calbindin-D28k markedly increased followed by a reduction in PC neurodegenerative morphology. Taken together, our data suggest that laser light induced HT is a novel non-invasive approach to treat SCA1 and maybe other polyglutamine disorders.

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Acknowledgments

This work was supported by R03 NS070065-01 grant from the NIH. Also, we would like to thank Dr. Gene Bidwell III for his involvement in the animal studies.

Conflict of Interest

There is no conflict of interest. The data reported in this manuscript has not been published or submitted for publication elsewhere. All authors have agreed to the contents of this article and there are no ethical issues involved.

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Authors and Affiliations

  1. Department of Neurology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS, 39216, USA

    Scoty M. Hearst, Qingmei Shao, Mariper Lopez & Parminder J. S. Vig

  2. Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA

    Scoty M. Hearst, Drazen Raucher & Parminder J. S. Vig

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  1. Scoty M. Hearst
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  2. Qingmei Shao
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Correspondence to Parminder J. S. Vig.

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Hearst, S.M., Shao, Q., Lopez, M. et al. Focused Cerebellar Laser Light Induced Hyperthermia Improves Symptoms and Pathology of Polyglutamine Disease SCA1 in a Mouse Model. Cerebellum 13, 596–606 (2014). https://doi.org/10.1007/s12311-014-0576-1

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