title: Focused cerebellar laser light induced hyperthermia improves symptoms and pathology of polyglutamine disease SCA1 in a mouse model.
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.
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS, 39216, USA.
authors.forename: Scoty M
authors.initials: SM
authors.lastname: Hearst
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Shao
authors.forename: Mariper
authors.initials: M
authors.lastname: Lopez
authors.forename: Drazen
authors.initials: D
authors.lastname: Raucher
authors.forename: Parminder J S
authors.initials: PJ
authors.lastname: Vig
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002467:Cell Nucleus / Q000378:metabolism; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D007150:Immunohistochemistry; D053685:Laser Therapy / Q000379:methods*; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D013696:Temperature; D016896:Treatment Outcome; D014617:Vacuoles / Q000473:pathology / Q000502:physiology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse