亨廷頓氏舞蹈病是一種常染色體顯性遺傳的神經(jīng)退行性疾病,，主要表現(xiàn)為運(yùn)動(dòng)障礙、認(rèn)知和精神紊亂，一般在發(fā)病后10-15年內(nèi)死亡。該疾病的病理特征是大腦紋狀體神經(jīng)元的漸進(jìn)性丟失,，但亨廷頓基因突變導(dǎo)致紋狀體神經(jīng)元選擇性死亡的機(jī)制還不清楚,，目前也沒有任何治療手段,。前人一系列研究發(fā)現(xiàn),，與大腦其他區(qū)域相比，舞蹈病病人的紋狀體區(qū)具有顯著升高的氧化應(yīng)激水平,，然而氧化應(yīng)激的來源和機(jī)制目前不清楚,。
中科院動(dòng)物所唐鐵山研究組利用酵母人工染色體轉(zhuǎn)基因舞蹈病（HD）模型鼠研究了HD細(xì)胞中線粒體Ca2+穩(wěn)態(tài)失衡與線粒體氧化損傷之間的關(guān)系,，結(jié)果表明HD細(xì)胞線粒體基質(zhì)中Ca2+濃度和活性氧的水平都顯著高于對(duì)照野生細(xì)胞,，提示HD線粒體中的Ca2+穩(wěn)態(tài)和活性氧信號(hào)都發(fā)生了紊亂。如果阻斷線粒體Ca2+攝入也同樣阻斷了線粒體中活性氧水平的升高,，表明HD細(xì)胞線粒體中氧化壓力的增高依賴于線粒體Ca2+的攝入,。同樣的結(jié)果也在HD小鼠模型的紋狀體神經(jīng)元和HD病人成纖維細(xì)胞中得到。
更為重要的是,，HD細(xì)胞中線粒體Ca2+過量攝入可以直接導(dǎo)致線粒體基因組DNA（mtDNA）損傷的顯著升高,。因此依賴于線粒體Ca2+攝入的氧化應(yīng)激和氧化損傷積累最終會(huì)導(dǎo)致線粒體的功能障礙和神經(jīng)細(xì)胞死亡。這項(xiàng)研究首次證實(shí)了舞蹈病神經(jīng)元線粒體Ca2+過度攝入/氧化應(yīng)激/mtDNA損傷三者之間存在的確切因果關(guān)系,。本研究也提示降低線粒體Ca2+攝入可以作為HD治療的一個(gè)策略,。鑒于Ca2+信號(hào)異常在多種神經(jīng)退行性疾病（如阿爾茲海默病,、帕金森病,、脊髓小腦共濟(jì)失調(diào)癥等）的病理發(fā)生中發(fā)揮著重要作用，本研究結(jié)果對(duì)于上述疾病治療手段的開發(fā)也具有重要的借鑒意義,。
該成果于2012年12月17日在線發(fā)表于J Biol Chem,。研究組博士研究生王久強(qiáng)為該論文第一作者，唐鐵山研究員為通訊作者,。合作者有北京大學(xué)程和平教授,、膜重點(diǎn)室孫欽秒和陳佺研究員以及北京基因組研究所郭彩霞研究員。該研究得到了科技部,、國家自然科學(xué)基金委和中國科學(xué)院的資助,。(生物谷Bioon.com)
doi: 10.1074/jbc.M112.407726
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Dysregulation of Mitochondrial Calcium Signaling and Superoxide Flashes Cause Mitochondrial Genomic DNA Damage in Huntington's Disease
Jiu-Qiang Wang1, Qian Chen1, Xianhua Wang2, Qiao-Chu Wang1, Yun Wang1, He-Ping Cheng2, Caixia Guo1, Qinmiao Sun1, Quan Chen1 and Tie-Shan Tang1,*
SUMMARY Huntingtons disease (HD) is an inherited, fatal neurodegenerative disorder characterized by the progressive loss of striatal medium spiny neurons. Indications of oxidative stress are apparent in brain tissues from both HD patients and HD mouse models; however, the origin of this oxidant stress remains a mystery. Here, we used a yeast artificial chromosome transgenic mouse model of HD (YAC128) to investigate the potential connections between dysregulation of cytosolic Ca2+ signaling and mitochondrial oxidative damage in HD cells. We found that YAC128 embryonic fibroblasts (MEFs) exhibit a strikingly higher level of mitochondrial matrix Ca2+ loading and elevated superoxide generation compared to WT cells, indicating that both mitochondrial Ca2+ signaling and superoxide generation are dysregulated in HD cells. The excessive mitochondrial oxidant stress is critically dependent on mitochondrial Ca2+ loading in HD cells, since blocking mitochondrial Ca2+ uptake abolished elevated superoxide generation. Similar results were obtained using neurons from HD model mice and fibroblast cells from HD patient. More importantly, mitochondrial Ca2+ loading in HD cells caused a 2-fold higher level of mitochondrial genomic DNA (mtDNA) damage due to the excessive oxidant generation. This study provides strong evidence to support a new causal link between dysregulated mitochondrial Ca2+ signaling, elevated mitochondrial oxidant stress and mtDNA damage in HD. Our results also indicate that reducing mitochondrial Ca2+ uptake could be a therapeutic strategy for HD.
