Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3?
Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3?
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DOI：
10.1093/hmg/ddq111
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发表时间：
2010-06-15
影响因子：
3.5
通讯作者：
de Almeida, Luis Pereira
中科院分区：
文献类型：
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作者：
Alves, Sandro;Nascimento-Ferreira, Isabel;de Almeida, Luis Pereira
马查多-约瑟夫病或脊髓小脑共济失调 3 型 (MJD/SCA3) 是一种致命的常染色体显性遗传疾病，由 MJD1 基因编码区的胞嘧啶-腺嘌呤-鸟嘌呤扩展引起。 RNA 干扰具有作为一种治疗方法的潜力，但引发了野生型 ataxin-3 (WT ATX3) 在 MJD 中的作用以及是否必须维持野生型蛋白表达的问题。为了解决这个问题，我们在 MJD 大鼠模型中过度表达并沉默 WT ATX3。我们发现，(i) WT ATX3 的过度表达并不能预防 MJD 病理，(ii) WT ATX3 的敲低不会加重 MJD 病理，(iii) ataxin-3 的非等位基因特异性沉默可大大降低 MJD 大鼠模型的神经病理。我们的研究结果表明，涉及非等位基因特异性沉默的治疗策略可能是安全有效的。
Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) is a fatal, autosomal dominant disorder caused by a cytosine-adenine-guanine expansion in the coding region of the MJD1 gene. RNA interference has potential as a therapeutic approach but raises the issue of the role of wild-type ataxin-3 (WT ATX3) in MJD and of whether the expression of the wild-type protein must be maintained. To address this issue, we both overexpressed and silenced WT ATX3 in a rat model of MJD. We showed that (i) overexpression of WT ATX3 did not protect against MJD pathology, (ii) knockdown of WT ATX3 did not aggravate MJD pathology and that (iii) non-allele-specific silencing of ataxin-3 strongly reduced neuropathology in a rat model of MJD. Our findings indicate that therapeutic strategies involving non-allele-specific silencing to treat MJD patients may be safe and effective.