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

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 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. Mutant TBP with polyglutamine expansion preferentially affects neuronal viability in SCA17 patients. Whether glia, the cells that support and protect neurons, contribute to neurodegeneration in SCA17 remains mostly unexplored. In this study, we provide both and evidence arguing that endogenous expression of mutant TBP in neurons and glia synergistically impacts neuronal survival. Hyperactivated inflammatory signaling pathways, particularly the NF-κB pathway, underlie glia-mediated neurotoxicity. Moreover, blocking NF-κB activity with small chemical inhibitors alleviated such neurotoxicity. Our study establishes glial dysfunction as an important component of SCA17 pathogenesis and suggests targeting glial inflammation as a potential therapeutic approach for SCA17 treatment.

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

“…Interestingly, Serpina3n expression was evident already in newborn mice, long before the onset of PCs degeneration and behavioral deficits in motor coordination, that appeared much later in one-year-old cerebella. Similarly, activated inflammatory pathways such as NF-kB were uncovered in mutant astrocytes in a cell culture model of SCA17 and their blocking was shown to ameliorate neurodegeneration [58].…”

“…Altogether, these results support a significant role of BG in SCA7 pathogenesis where both cell-autonomous and non-cell autonomous mechanisms are likely to contribute to neurodegeneration in a tightly interconnected network between neurons and BG. Similarly, neurodegeneration in SCA17 was reported to depend on the concomitant expression of the mutant TATA-binding protein (TBP) gene in both neurons and astrocytes, while the mutant gene expressed in either of the two cell populations only caused a mild PCs degeneration [58].…”

“…Cerebellar astrogliosis is not only among the first cell-intrinsic effects of the expression of ataxia-related genes in cerebellar astrocytes [58,72,73] but it is also probably one of the astrocytes' earliest responses to the abnormal behaviors of mutant neurons. Early astrocyte activation was indeed observed in both the cerebellar nuclei (CN) and cortex in a SCA21 mouse model in which the mutated gene TMEM240 was expressed only in neurons [74].…”

“…Inflammation and astrogliosis also appear as crucial players in disease progression. In this context, anti-inflammatory astroglia-based therapeutic approaches have been proposed for both SCA1 and SCA17 [58,76]. Yet, the evidence that intracerebroventricular injections of IL-1 receptor antagonist (IL-1ra) in EAE mice reduced motor deficits are very promising in view of responsiveness to anti-inflammatory treatments also in other forms of ataxia [49].…”

Gray Matter Heterotopia, Mental Retardation, Developmental Delay, Microcephaly, and Facial Dysmorphisms in a Boy with Ring Chromosome 6: A 10-Year Follow-Up and Literature Review

“…morphic CAG repeat in its variable N-terminal domain, and expansion of this repeat may lead to late-onset neurological disorders such as spinocerebellar ataxia 17 [Hsu et al, 2014;Yang et al, 2017], Parkinson disease [Choubtum et al, 2016], and Huntington disease-like symptoms [Stevanin et al, 2003]. In addition, TBP -related defects were also found in patients with mental retardation, which appeared to closely correlate to the manifestations of these patients [Rooms et al, 2006].…”