LRRK2 Parkinson disease mutations enhance its microtubule association
LRRK2 Parkinson disease mutations enhance its microtubule association
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DOI：
10.1093/hmg/ddr526
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发表时间：
2012-02-15
影响因子：
3.5
通讯作者：
Dauer, William T.
中科院分区：
文献类型：
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作者：
Kett, Lauren R.;Boassa, Daniela;Dauer, William T.
富亮氨酸重复激酶2 （LRRK2）的显性错义突变是帕金森病（PD）最常见的遗传原因，全基因组关联研究发现LRRK2序列变异是散发性PD的危险因素。完整的激酶功能似乎对LRRK2 PD突变体的毒性至关重要，但我们对LRRK2如何导致神经变性的理解仍然有限。我们发现大多数LRRK2 PD突变体异常增强LRRK2寡聚化，导致其在细胞系转染或原代神经元培养中形成丝状结构。引人注目的是，包括免疫电子显微镜和电子显微镜断层扫描在内的超结构分析表明，这些细丝由LRRK2组成，以有序的周期性方式招募到细胞微管网络的一部分。与lrrk2相关的神经退行性变一样，微管结合需要完整的激酶功能和WD40结构域，可能将微管结合与神经退行性变联系起来。我们的观察发现了LRRK2 PD突变的新作用，并强调了微管在LRRK2相关神经变性发病机制中的潜在作用。
Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic causes of Parkinson disease (PD) and genome-wide association studies identify LRRK2 sequence variants as risk factors for sporadic PD. Intact kinase function appears critical for the toxicity of LRRK2 PD mutants, yet our understanding of how LRRK2 causes neurodegeneration remains limited. We find that most LRRK2 PD mutants abnormally enhance LRRK2 oligomerization, causing it to form filamentous structures in transfections of cell lines or primary neuronal cultures. Strikingly, ultrastructural analyses, including immuno-electron microscopy and electron microscopic tomography, demonstrate that these filaments consist of LRRK2 recruited onto part of the cellular microtubule network in a well-ordered, periodic fashion. Like LRRK2-related neurodegeneration, microtubule association requires intact kinase function and the WD40 domain, potentially linking microtubule binding and neurodegeneration. Our observations identify a novel effect of LRRK2 PD mutations and highlight a potential role for microtubules in the pathogenesis of LRRK2-related neurodegeneration.