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• W4220996178 abstract "Spinocerebellar ataxia type 3 (SCA 3) is a rare devastating neurodegenerative disorder caused by the expansion of CAG repeats in exon 10 of the ataxin-3 (ATXN3) gene, resulting in the expression of polyglutamine (polyQ) expanded mutant protein (mATXN3) (reviewed in Paulson).1 PolyQ aggregation in general has been shown to follow seeded growth polymerization kinetics with either the size or the concentration of an aggregation intermediate being critical for the fibrillization process.2, 3 Therefore, it is reasonable to argue that strategies aiming at decreasing the amount of aggregation prone mATXN3 species, or ATXN3 in general, could provide direct therapeutic benefit. Using mouse and other model organisms, we and others have shown that decreased ATXN3 does not lead to apparent morphological abnormalities or premature death.4 Allele-specific exon skipping resulted in lower mATXN3 levels and aggregate load in a SCA3-YAC mouse model.5 Similar results have been observed with various micro RNA approaches, suggesting that strategies to decrease ATXN3 expression in human SCA3 patients would be safe and of direct therapeutic value.6-9 We developed a quantitative assay based on a fluorophore-labeled, highly specific antibody to ATXN3 and recombinant human ATXN3 purified to homogeneity, serving as standard to determine absolute amounts of ATXN3 and observed considerable variation of normal and mATXN3 in human peripheral blood mononuclear cells (PBMC). Between 0.5 and 3 nanograms ATXN3 were present per microgram protein (Supplementary Fig. 1). The well-known inverse correlation between CAG repeat length and age at onset was reflected in our cohort, suggesting that the cohort was representative despite the small number. No clear cut correlation with age, sex, or the severity of ataxia (scale for the assessment and rating of ataxia score) became apparent with absolute amounts of normal or mATXN3; similar to what has been observed recently (data not shown).10, 11 Independent of the absolute amount, however, the ratio of normal to mATXN3 correlated with the age at onset of motor symptoms (ie, the more mATXN3 relative to normal ATXN3 was present in PBMC, the earlier the age at onset (Fig. 1). This phenomenon points to the importance of the individual relative proportion of expanded, dysfunctional protein, and fits with the idea of a toxic gain of function of mATXN3. As we observed no clear cut correlation with age and little variation with repeated sampling, measurement of ATXN3 in PBMC appears as a feasible tool to determine the amount of both normal and mATXN3 in an individual over time and therefore, to evaluate the effect of compounds or molecular tools, which supposedly lower neuronal ATXN3 expression in a clinical trial. It will be interesting to evaluate a putative change of ATXN3 expression in PBMC after systemic (or intrathecal) application of a canonical drug or antisense-oligonucleotides, because we are concerned that the amount of ATXN3 in cerebrospinal fluid (CSF) might be to low to measure, even with a highly specific and sensitive assay. Whether the relative amounts of ATXN3 will develop into a useful biomarker for SCA3 (ie, whether this ratio has a prognostic value in individuals at risk before the onset of obvious motor signs) remains to be determined in larger longitudinal cohorts. Appendix S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W4220996178 date "2022-03-12" @default.
• W4220996178 modified "2023-09-26" @default.
• W4220996178 title "The Ratio of Expanded to Normal Ataxin 3 in Peripheral Blood Mononuclear Cells Correlates with the Age at Onset in Spinocerebellar Ataxia Type 3" @default.
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• W4220996178 doi "https://doi.org/10.1002/mds.28962" @default.
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