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Query: UNIPROT:P06889 (
Mol
)
630,302
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Spinocerebellar ataxia
type 3 (SCA3) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene encoding the ataxin-3 protein. Despite extensive research the exact pathogenic mechanisms of SCA3 are still not understood in depth. In the present study, to gain insight into the toxicity induced by the expanded CAG repeats in SCA3, we comprehensively investigated repeat-associated non-ATG (RAN) translation in various cellular models expressing translated or non-canonically translated ATXN3 sequences with an increasing number of CAG repeats. We demonstrate that two SCA3 RAN proteins, polyglutamine (polyQ) and polyalanine (polyA), are found only in the case of CAG repeats of pathogenic length. Despite having distinct cellular localization, RAN polyQ and RAN polyA proteins are very often coexpressed in the same cell, impairing nuclear integrity and inducing apoptosis. We provide for the first time mechanistic insights into SCA3 RAN translation indicating that ATXN3 sequences surrounding the repeat region have an impact on SCA3 RAN translation initiation and efficiency. We revealed that RAN translation of polyQ proteins starts at non-cognate codons upstream of the CAG repeats, whereas RAN polyA proteins are likely translated within repeats. Furthermore, integrated stress response activation enhances SCA3 RAN translation. Our findings suggest that the ATXN3 sequence context plays an important role in triggering SCA3 RAN translation and that SCA3 RAN proteins may cause cellular toxicity.
J
Mol
Biol 2020 Nov 04
PMID:RAN Translation of the Expanded CAG Repeats in the SCA3 Disease Context. 3315 84
Spinocerebellar ataxia
(SCA) 42 is caused by a mutation in CACNA1G, which encodes the low voltage-gated calcium channel Ca
V
3.1 (T-type). Patients with SCA42 exhibit a pure form of cerebellar ataxia. We encountered a patient with the p.Arg1715His mutation, suffering from intractable resting tremor, particularly head tremor. This symptom improved with the administration of low-dose of zonisamide (ZNS), a T-type calcium channel blocker effective for treating Parkinson's disease and epilepsy. Previous electrophysiological studies showed that the voltage dependence of this mutant Ca
V
3.1 was shifted toward the positive potential. This abnormal shift was considered a factor related to disease onset and symptoms. In this study, we performed whole-cell recordings of GFP-expressing HEK293T cells that expressed wild-type or mutant Ca
V
3.1 and investigated the changes in the abnormal shift of voltage dependence of the mutant Ca
V
3.1. The results showed that ZNS in an amount equivalent to the patient's internal dose significantly ameliorated the abnormal shift in the mutant Ca
V
3.1, giving values close to those in the wild-type. On the other hand, ZNS did not affect the voltage dependence of wild-type Ca
V
3.1. Because Ca
V
3.1 is known to be involved in tremogenesis, modulation of the voltage dependence of mutant Ca
V
3.1 by ZNS might have contributed to improvement in the intractable tremor of our patient with SCA42. Moreover, efonidipine, another T-type calcium channel blocker, had no effect on tremors in our patient with SCA42 and did not improve the abnormal shift in the voltage dependence of the mutant Ca
V
3.1. This indicates that ZNS is distinct from other T-type calcium channel blockers in terms of modulation of the voltage dependence of the mutant Ca
V
3.1.
Mol
Brain 2020 11 26
PMID:Zonisamide can ameliorate the voltage-dependence alteration of the T-type calcium channel Ca
V
3.1 caused by a mutation responsible for spinocerebellar ataxia. 3324 96
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