SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications

Abstract

Spinocerebellar ataxia type 8 (SCA8) involves bidirectional expression of CUG (ATXN8OS) and CAG (ATXN8) expansion transcripts. The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad. In the present study, we assessed the SCA8 repeat size ranges in Taiwanese Parkinson's disease, Alzheimer's disease and atypical parkinsonism and investigated the genetic variation modulating ATXN8 expression. Thirteen large SCA8 alleles and a novel ATXN8 -62 G/A promoter SNP were found. There is a significant difference in the proportion of the individuals carrying SCA8 larger alleles in atypical parkinsonism (P = 0.044) as compared to that in the control subjects. In lymphoblastoid cells carrying SCA8 large alleles, treatment of MG-132 or staurosporine significantly increases the cell death or caspase 3 activity. Although expressed at low steady-state, ATXN8 expression level is significantly higher (P = 0.012) in cells with SCA8 large alleles than that of the control cells. The ATXN8 transcriptional activity was significantly higher in the luciferase reporter construct containing the -62G allele than that containing the -62A allele in both neuroblastoma and embryonic kidney cells. Therefore, our preliminary results suggest that ATXN8 gene -62 G/A polymorphism may be functional in modulating ATXN8 expression.

Coexisting huntingtin and SCA8 repeat expansion: Case report of a severe complex neurodegenerative syndrome

“…Severe ataxia with inability to walk independently is usually not a typical feature for HD or SCA8 at this disease stage. Wu et al detected SCA8 expanded alleles in PD and atypical Parkinsonism suggesting that SCA8 CTG repeat expansion may play a role in the development of sporadic PD or atypical Parkinsonism [2]. The fact that Parkinsonian symptoms of our patient remained unresponsive to dopaminergic medication supports the hypothesis of possible involvement of SCA8 in the pathogenesis of atypical Parkinsonism.…”

“…As there is an overlapping gene ATXN8, the polyglutamine expansion protein possibly contributes through toxic effects, too [10]. The clinical presentation of large repeat expansions is variable; the phenotype spectrum ranges from healthy subjects, patients with cerebellar ataxia to patients with typical and atypical Parkinson disease [2]. In addition coexistence with SCA1, SCA6, 16q-ADCA, FRDA have been reported.…”

“…The reported repeat lengths associated with ataxia usually range from 85 to 130 [2]. In neurodegenerative disorders such as sporadic Parkinson disease (PD) [2] and in ataxias like SCA1, SCA6, 16q-ADCA, and Friedreich's ataxia (FRDA) a rare coexistence of the repeat expansion in the ATXN8 gene has been observed [3][4][5][6]. On the basis of clinical data and neuropathological findings a common pathogenesis has been suggested for SCA6, SCA8 and 16q-ADCA [4].…”

“…The clinical symptoms include cerebellar ataxia, dysarthria, dysphagia, sensory neuropathy and cognitive impairment. The reported repeat lengths associated with ataxia usually range from 85 to 130 [2]. In neurodegenerative disorders such as sporadic Parkinson disease (PD) [2] and in ataxias like SCA1, SCA6, 16q-ADCA, and Friedreich's ataxia (FRDA) a rare coexistence of the repeat expansion in the ATXN8 gene has been observed [3][4][5][6].…”

Parkinsonism in Spinocerebellar Ataxia

“…Wu et al detected an abnormal expansion of SCA8 in four patients with typical PD (1.5%) from among 264 patients with PD [ 19 ]. The range of the SCA8 repeat size was analyzed in a Taiwanese PD cohort, and large SCA8 alleles (66–120 repeats) and a novel ATXN8 −62 G/A promoter SNP were found [ 78 ]. The same group also performed a structural analysis in a cohort of 569 PD cases and 547 ethnically matched controls, and they found that individuals carrying the AA genotype exhibited a decreased risk of developing PD than those with the GG + GA phenotypes [ 71 ].…”