A Neurological Disease Caused By an Expanded CAG Trinucleotide Repeat in The TATA-Binding Protein Gene: A New Polyglutamine Disease?
Department of Neurology, Niigata University, Japan. Human Molecular Genetics
(Impact Factor: 6.39).
To investigate whether the expansion of CAG repeats of the TATA-binding protein (TBP) gene is involved in the pathogenesis of neurodegenerative diseases, we have screened 118 patients with various forms of neurological disease and identified a sporadic-onset patient with unique neurologic symptoms consisting of ataxia and intellectual deterioration associated with de novo expansion of the CAG repeat of the TBP gene. The mutant TBP with an expanded polyglutamine stretch (63 glutamines) was demonstrated to be expressed in lymphoblastoid cell lines at a level comparable with that of wild-type TBP. The CAG repeat of the TBP gene consists of impure CAG repeat and the de novo expansion involves partial duplication of the CAG repeat. The present study provides new insights into sporadic-onset trinucleotide repeat diseases that involve de novo CAG repeat expansion.
Available from: Jifeng Guo
- "Although little is known about the function of MyoD and its relationship with TBP in adult muscle cells, our studies suggest that mutant TBP affects muscle only in adult mice. This is because our SCA17 mice, like juvenile SCA17 patients with 63Q or 66Q in TBP (Koide et al., 1999; Maltecca et al., 2003), are born normally without muscle weakness, with muscle degeneration occurring several months later. Mutant TBP accumulates in muscle nuclei and becomes misfolded with age, consistent with its late-onset effect on MyoD function in adult muscles. "
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ABSTRACT: In polyglutamine (polyQ) diseases, large polyQ repeats cause juvenile cases with different symptoms than those of adult-onset patients, who carry smaller expanded polyQ repeats. The mechanisms behind the differential pathology mediated by different polyQ repeat lengths remain unknown. By studying knockin mouse models of spinal cerebellar ataxia-17 (SCA17), we found that a large polyQ (105 glutamines) in the TATA-box-binding protein (TBP) preferentially causes muscle degeneration and reduces the expression of muscle-specific genes. Direct expression of TBP with different polyQ repeats in mouse muscle revealed that muscle degeneration is mediated only by the large polyQ repeats. Different polyQ repeats differentially alter TBP's interaction with neuronal and muscle-specific transcription factors. As a result, the large polyQ repeat decreases the association of MyoD with TBP and DNA promoters. Our findings suggest that specific alterations in protein interactions by large polyQ repeats may account for the unique pathology in juvenile polyQ diseases.
- "TBP/SCA17 with CAG repeat expansion tract was found at the TATAbinding protein gene (TBP) on chromosome 6q27 in an isolated patient with symptoms of ataxia and intellectual deterioration . TBP repeat expansions have since been described in 4 Japanese families affected by this new type of ataxia with dementia known as SCA17 . "
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ABSTRACT: Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range, diseases range, large normal alleles (LNAs). In this study, we assessed the CAG repeats at SCA17 in 188 clinical SCA patients and 100 individuals without any neurological signs. This highly polymorphic population displayed high variability in the CAG repeats and ranged from 19-38 CAG repeats in patients with mode of 20 and 19-32 CAG repeats in controls with mode of 24. The triplet repeat expansion was not detected in any of the 188 patients, as per the reference pathogenic range (>43 repeats); however, 2.7% of the patients had >33 CAG repeats with a clinical phenotype close to what is expected of SCA 17 patients. The findings of this study implicate a more sophisticated interpretation of SCA17 gene and raise the question about the diagnostic thresh hold between normal and expanded repeats in our population.
Available from: Kuo-Hsuan Chang
- "Spinocerebellar ataxias (SCAs) are a large, complex group of heterogeneous autosomal dominant neurodegenerative disorders characterized by cerebellar dysfunction alone or in combination with other neurological abnormalities . Among them, the expansions of CAG trinucleotide repeats encoding a polyglutamine (polyQ) stretch have been shown to cause dominantly inherited SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and dentatorubropallidoluysianatrophy (DRPLA)       . These polyQ-mediated genetic disorders in SCAs have shown selective progressive degeneration of the cerebellum, brainstem, and spinal tract, with prominent pathological hallmark of intranuclear and cytoplasmic accumulation of aggregated polyQ proteins inside degenerated neurons . "
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ABSTRACT: Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 as well as Huntington's disease are a group of neurodegenerative disorders caused by expanded CAG repeats encoding a long polyglutamine (polyQ) tract in the respective proteins. Evidence has shown that the accumulation of intranuclear and cytoplasmic misfolded polyQ proteins leads to apoptosis and cell death. Thus suppression of aggregate formation is expected to inhibit a wide range of downstream pathogenic events in polyQ diseases. In this study, we established a high-throughput aggregation screening system using 293 ATXN3/Q75-GFP cells and applied this system to test the aqueous extract of Paeonia lactiflora (P. lactiflora) and its constituents. We found that the aggregation can be significantly prohibited by P. lactiflora and its active compound paeoniflorin. Meanwhile, P. lactiflora and paeoniflorin upregulated HSF1 and HSP70 chaperones in the same cell models. Both of them further reduced the aggregation in neuronal differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate how P. lactiflora and paeoniflorin are likely to work on polyQ-aggregation reduction and provide insight into the possible working mechanism of P. lactiflora in SCA3. We anticipate our paper to be a starting point for screening more potential herbs for the treatment of SCA3 and other polyQ diseases.
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