Glial S100B protein modulates mutant ataxin-1 aggregation and toxicity: TRTK12 peptide, a potential candidate for SCA1 therapy.

摘要: Non-cell autonomous involvement of glial cells in the pathogenesis polyglutamine diseases is gaining recognition ataxia field. We previously demonstrated that Purkinje (PCs) disease spinocerebellar ataxia-1 (SCA1) contain cytoplasmic vacuoles rich Bergmann protein S100B. The vacuolar formation SCA1 PCs accompanied with an abnormal morphology dendritic spines. In addition, S100B messenger RNA (mRNA) expression levels are significantly high cerebella asymptomatic transgenic (Tg) mice and increase further age when compared age-matched wild-type animals. This higher mRNA positively correlates number vacuoles. To characterize function pathology, we explored effects on GFP-ataxin-1 (ATXN1) expanded polyglutamines [82Q] HEK stable cell line. Externally added to these induced S100B-positive similar those seen vivo. Further, found both externally internally expressed reduced GFP-ATXN1[82Q] inclusion body formation. contrast, addition inhibitory peptide TRTK12 reversed S100B-mediated effects. Interestingly, Tg mice, containing also showed lack nuclear inclusions, whereas without contained inclusions. Additionally, treatment growth cerebellar slice cultures prepared from mice. Moreover, intranasal administration particulate fractions, displayed a significant improvement their performance deficit Rotarod test. Taken together, our results suggest may augment degenerative changes by modulating mutant ataxin-1 toxicity/solubility through unknown signaling pathway.