Junior Researcher Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Russia
Abstract: Spinocerebellar ataxia type 17 (SCA17) is an orphan neurodegenerative disease caused by trinucleotide repeat expansion in the ТВР gene. SCA17 is characterized by severe symptoms and irreversible progression, leading to disabilities and death. The mechanisms of the disease pathogenesis are unclear. It is thought that neuroinflammation, driven primarily by proinflammatory reactive astrocytes, may contribute to SCA17 pathogenesis. To explore this hypothesis, we generated astrocytes from induced pluripotent stem cells (iPSCs) derived from TBP mutation carriers. This included two lines from SCA17 patients and one from an asymptomatic carrier. SCA17 astrocytes showed identical morphology and astroglial markers expression to the healthy controls. However, SCA17 astrocytes demonstrated elevated expression of the proinflammatory cytokine TNF. Analyses of transcriptome and secretome revealed significant upregulation of immune pathways in SCA17 astrocytes, with a stronger proinflammatory response observed in astrocytes from symptomatic patients than in those from the asymptomatic carrier. Our findings indicate that the TBP mutation induces a proinflammatory phenotype in astrocytes, suggesting a potential role of astrocytic immune dysregulation in the pathogenesis of SCA17.
Funding Source: This study was supported by a grant 075-15-2019-1669 from the Ministry of Science and Higher Education of the Russian Federation.
