Expansion of the polyQ repeats in THAP11 forms intranuclear aggregation and causes cell G0/G1 arrest

Abstract

Polyglutamine diseases are a group of neurodegenerative disorders caused by expansion of a CAG repeat that encodes polyglutamine in each respective disease gene. The transcription factor THAP11, a member of THAP family, is involved in cell growth, ES cell pluripotency and embryogenesis. Previous studies suggest that THAP11 protein contains a 29-residue repeat polyglutamine motif and the number of polyglutamine ranges from 20 to 41 in Indian population. We have investigated the CAG numbers at the THAP11 locus in normal individuals and neurodegenerative disease patients of Chinese Han population and a 38Q expansion (THAP11(38Q)) was found in patients. Using fluorescence confocal-based cell imaging, THAP11(38Q) protein formed intranuclear inclusions easier than THAP11(29Q) in PC12 cells. Enhanced toxicity was investigated in THAP11(38Q)-expressing cells by growth inhibition and G0/G1 arrest. CREB-mediated transcription activity was inhibited by THAP11(38Q). The transcription factor, TBP, coactivator CBP, and chaperon protein, HSP70, could be recruited to THAP11(38Q). These results indicate that expansion of the polyglutamine in THAP11 forms intracellular aggregation and is toxic in PC12 cells, suggesting a putative role of THAP11 in polyglutamine disease.

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

“…Our finding updated the polyQ disease spectrum, of which the most recent phenotype (ie, Huntington disease-like 2) was identified more than two decades ago. 22 The size of CAG repeats in THAP11 was not more than 41 in the Indian healthy population, 34 in the Chinese Han healthy population, 12,13 38 in healthy control subjects, and 42 in the non-SCA cohort in this study. In contrast, CAG expansion ≥45 repeats in THAP11 was associated with ataxia phenotype.…”

“…The protein encoded by THAP11 gene regulates cell cycle, proliferation, transcription, and cobalamin metabolism. THAP11 gene was reported as a potential candidate for progressive ataxia in the Indian and SCA in the Chinese cohorts, 12,13 but not identified as a pathogenic gene yet. In this study, we performed long-read whole-genome sequencing (LRS) combined with linkage analysis in a five-generation Chinese family and identified a novel SCA subtype as a result of CAG repeat expansion in exon 1 of THAP11 gene, which was validated in another pedigree.…”

Selection pressure on human STR loci and its relevance in repeat expansion disease

“…Hyper-expanded poly-Q stretches are known to cross-liked to other proteins such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which form aggregates (Guzhova et al 2011). Moreover, longer poly-Q repeats in human THAP11 are associated with more intracellular aggregations (Yin et al 2014). This leads to conformational change in a poly-Q length-dependent manner (Vachharajani et al 2012).…”

Ronin overexpression induces cerebellar degeneration in a mouse model of ataxia

“…Future studies are needed to clarify whether expansion of the polyQ region in Ronin might lead to more severe outcomes. CAG repeat length differences have been described in both normal individuals and patients with neurological disorders, ranging from 10-41 ( Yin et al, 2014 ; Pandey, et al, 2004 ; Butland et al, 2007 ). A repeat length of 29 is the most frequent (∼70%) followed by 28 repeats (∼20%), with no significant difference between normal and diseased individuals.…”

“…A repeat length of 29 is the most frequent (∼70%) followed by 28 repeats (∼20%), with no significant difference between normal and diseased individuals. Interestingly, a 38Q repeat was detected in two neurodegenerative disease patients, and expansion of the glutamine repeat in vitro leads to increased formation of nuclear aggregates in PC12 cells ( Yin et al, 2014 ). Given the ataxic phenotype in our mouse model, we predict that further analyses of human Ronin, its binding partners and its binding sites in target gene promoters might reveal novel mutations in the spectrum of neurodegenerative disease.…”