Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17

• Authors: Yang Yang, Central South University; Su Yang, Emory University; Jifeng Guo, Central South University; Yiting Cui, Central South University; Beisha Tang, Central South University; Xiao-Jiang Li, Emory University; Shi Hua Li, Emory University
• Journal Title: Journal of Neuroscience Nursing
• Volume: Volume 37, Number 38
• Publisher: Lippincott, Williams & Wilkins | 2017-09-20, Pages 9101-9115
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1523/JNEUROSCI.0111-17.2017
• Subjects: Biology, Genetics; Biology, Neuroscience
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; glia; neurodegeneration; neuron; polyglutamine; TBP; transcription; DISEASE-LIKE PHENOTYPE; HUNTINGTONS-DISEASE; MUTANT HUNTINGTIN; TRINUCLEOTIDE REPEAT; MOUSE MODEL; ANDROGEN RECEPTOR; SCA17 MICE; IN-VIVO; EXPRESSION; NEURODEGENERATION

Abstract

Spinocerebellar ataxia 17 (SCA17) is caused by polyglutamine (polyQ) repeat expansion in the TATA-binding protein (TBP) and is among a family of neurodegenerative diseases in which polyQ expansion leads to preferential neuronal loss in the brain. Although previous studies have demonstrated that expression of polyQ-expanded proteins in glial cells can cause neuronal injury via noncell-autonomous mechanisms, these studies investigated animal models that overexpress transgenic mutant proteins. Since glial cells are particularly reactive to overexpressed mutant proteins, it is important to investigate the in vivo role of glial dysfunction in neurodegeneration when mutant polyQ proteins are endogenously expressed. In the current study, we generated two conditional TBP-105Q knock-in mouse models that specifically express mutant TBP at the endogenous level in neurons or in astrocytes. We found that mutant TBP expression in neuronal cells or astrocytes alone only caused mild neurodegeneration, whereas severe neuronal toxicity requires the expression of mutant TBP in both neuronal and glial cells. Coculture of neurons and astrocytes further validated that mutant TBP in astrocytes promoted neuronal injury. We identified activated inflammatory signaling pathways in mutant TBP-expressing astrocytes, and blocking nuclear factor κB (NF-κB) signaling in astrocytes ameliorated neurodegeneration. Our results indicate that the synergistic toxicity of mutant TBP in neuronal and glial cells plays a critical role in SCA17 pathogenesis and that targeting glial inflammation could be a potential therapeutic approach for SCA17 treatment.