Apoptotic mechanisms in mutant LRRK2-mediated cell death
Apoptotic mechanisms in mutant LRRK2-mediated cell death
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DOI：
10.1093/hmg/ddm080
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发表时间：
2007-06-01
影响因子：
3.5
通讯作者：
Barone, Paolo
中科院分区：
文献类型：
--
作者：
Iaccarino, Ciro;Crosio, Claudia;Barone, Paolo
富含亮氨酸重复激酶 2 (LRRK2) 的基因编码突变会导致常染色体显性遗传性帕金森病。病理突变与 LRRK2 激酶活性的增加有关，尽管其生理底物尚未确定。我们在此报告的数据表明，与疾病相关的突变体 LRRK2 细胞毒性是由于线粒体依赖性细胞凋亡造成的。突变体 LRRK2 的瞬时转染会导致神经元死亡，并伴有明显的细胞凋亡迹象。可溶性半胱天冬酶抑制剂或 Apaf1 的基因消除可保护细胞免于凋亡。此外，我们探索了 LRRK2 中两个蛋白结构域（LRR 和 WD40）的功能，并证明这些蛋白结构域的缺乏对突变体 LRRK2 诱导的线粒体功能障碍具有保护作用。
Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinson's disease. The pathological mutations have been associated with an increase of LRRK2 kinase activity, although its physiological substrates have not been identified yet. The data we report here demonstrate that disease-associated mutant LRRK2 cell toxicity is due to mitochondria-dependent apoptosis. Transient transfeclion of mutant LRRK2 leads to neuronal death with clear apoptotic signs. Soluble caspase inhibitors or the genetic ablation of Apaf1 protects cells from apoptotic death. Moreover, we explored the function of two protein domains in LRRK2 (LRR and WD40) and demonstrate that the lack of these protein domains has a protective effect on mitochondria dysfunctions induced by mutant LRRK2.