Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.
Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.
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DOI：
10.1371/journal.pgen.1004834
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发表时间：
2015-01
期刊：
影响因子：
4.5
通讯作者：
Sarkar PS
中科院分区：
文献类型：
--
作者：
Gao R;Liu Y;Silva-Fernandes A;Fang X;Paulucci-Holthauzen A;Chatterjee A;Zhang HL;Matsuura T;Choudhary S;Ashizawa T;Koeppen AH;Maciel P;Hazra TK;Sarkar PS
脊髓小脑性共济失调3型（SCA 3），也称为马查多-约瑟夫病（MJD），是一种无法治疗的常染色体显性遗传性神经退行性疾病，也是世界范围内最常见的遗传性共济失调。SCA 3中的突变是染色体基因座14q32.1处ATXN 3基因C-末端编码区中多态性CAG三核苷酸重复序列的扩增。编码扩展的谷氨酰胺（polyQ）序列的突变体ATXN 3蛋白在体内与多种蛋白相互作用，并作为聚集体沉积在SCA 3脑中。大量文献表明，沉积在polyQ聚集体中的天然ATNX 3相互作用蛋白的功能丧失有助于SCA 3中的细胞毒性、全身性神经变性和致病机制。尽管如此，对SCA 3的疾病病因学的重要理解，突变体ATXN 3中polyQ扩增诱导SCA 3神经变性的分子机制仍然难以捉摸。在本研究中，我们发现，必需的DNA链断裂修复酶PNKP（多核苷酸激酶3 '-磷酸酶）与突变体ATXN 3相互作用，并被其灭活，导致DNA修复效率低下，DNA损伤/链断裂的持续积累，以及随后SCA 3中DNA损伤反应共济失调毛细血管扩张突变（ATM）信号通路的慢性激活。我们报道了持续积累的DNA损伤/链断裂和丝氨酸/苏氨酸激酶ATM和下游p53和蛋白激酶C-δ促凋亡通路的慢性激活触发SCA 3中的神经元功能障碍并最终导致神经元死亡。无论是PNKP过表达或药物抑制ATM显着阻断突变ATXN 3介导的细胞死亡。突变体ATXN 3诱导DNA损伤并放大促死亡信号通路的机制的发现为SCA 3中PNKP失活引起的神经变性提供了分子基础，并首次提供了可能的治疗方法。脊髓小脑性共济失调3型（SCA 3）是一种无法治愈的神经退行性疾病，也是世界范围内最常见的显性遗传性共济失调。SCA 3由ATXN 3基因编码区中CAG三核苷酸重复序列的扩增引起。扩增的CAG序列编码一系列氨基酸谷氨酰胺;突变体ATXN 3在体内与多种蛋白质相互作用，在SCA 3大脑中产生不溶性聚集体。据认为，聚集蛋白的功能丧失导致SCA 3中的细胞毒性和神经变性。尽管在理解SCA 3的病因学方面取得了重大进展，但突变蛋白触发SCA 3大脑中神经元死亡的分子机制仍然未知。我们现在报告突变ATXN 3蛋白与PNKP（多核苷酸激酶3 '-磷酸酶）相互作用并使其失活，PNKP是一种必需的DNA链断裂修复酶。这种失活导致DNA损伤的持续积累，以及SCA 3中DNA损伤响应ATM信号通路的慢性激活。我们的工作表明，持续的DNA损伤/链断裂和ATM的慢性激活触发SCA 3中的神经元死亡。突变体ATXN 3诱导DNA损伤并放大促死亡途径的机制的发现为SCA 3中的神经变性提供了分子基础，并可能最终为其治疗提供了分子基础。
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an untreatable autosomal dominant neurodegenerative disease, and the most common such inherited ataxia worldwide. The mutation in SCA3 is the expansion of a polymorphic CAG tri-nucleotide repeat sequence in the C-terminal coding region of the ATXN3 gene at chromosomal locus 14q32.1. The mutant ATXN3 protein encoding expanded glutamine (polyQ) sequences interacts with multiple proteins in vivo, and is deposited as aggregates in the SCA3 brain. A large body of literature suggests that the loss of function of the native ATNX3-interacting proteins that are deposited in the polyQ aggregates contributes to cellular toxicity, systemic neurodegeneration and the pathogenic mechanism in SCA3. Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive. In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3’-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage/strand breaks, and subsequent chronic activation of the DNA damage-response ataxia telangiectasia-mutated (ATM) signaling pathway in SCA3. We report that persistent accumulation of DNA damage/strand breaks and chronic activation of the serine/threonine kinase ATM and the downstream p53 and protein kinase C-δ pro-apoptotic pathways trigger neuronal dysfunction and eventually neuronal death in SCA3. Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3-mediated cell death. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment. Spinocerebellar ataxia type 3 (SCA3) is an untreatable neurodegenerative disease, and the most common dominantly inherited ataxia worldwide. SCA3 is caused by expansion of a CAG tri-nucleotide repeat sequence in the ATXN3 gene’s coding region. The expanded CAG sequences encode a run of the amino acid glutamine; the mutant ATXN3 interacts with multiple proteins in vivo to create insoluble aggregates in SCA3 brains. It is thought that the loss of function of the aggregated proteins contributes to cellular toxicity and neurodegeneration in SCA3. Despite significant progress in understanding SCA3’s etiology, the molecular mechanism by which the mutant protein triggers the death of neurons in SCA3 brains remains unknown. We now report that the mutant ATXN3 protein interacts with and inactivates PNKP (polynucleotide kinase 3’-phosphatase), an essential DNA strand break repair enzyme. This inactivation results in persistent accumulation of DNA damage, and chronic activation of the DNA damage-response ATM signaling pathway in SCA3. Our work suggests that persistent DNA damage/strand breaks and chronic activation of ATM trigger neuronal death in SCA3. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death pathways provides a molecular basis for neurodegeneration in SCA3, and perhaps ultimately for its treatment.
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