Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons.
Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons.
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DOI：
10.1016/j.nbd.2017.12.005
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发表时间：
2018-03
影响因子：
6.1
通讯作者：
LaVoie MJ
中科院分区：
文献类型：
--
作者：
Schapansky J;Khasnavis S;DeAndrade MP;Nardozzi JD;Falkson SR;Boyd JD;Sanderson JB;Bartels T;Melrose HL;LaVoie MJ
多结构域激酶LRRK 2的错义突变会导致迟发性家族性帕金森病。它们最常见的是典型的蛋白质病，其形式为路易体和由不溶性α-突触核蛋白组成的路易神经突，但在极少数情况下也可表现为tau蛋白病。LRRK 2的正常功能仍然难以捉摸，其突变的细胞后果也是如此。来自LRRK 2无效模型生物体和LRRK 2抑制剂处理的动物的数据支持LRRK 2在调节溶酶体功能中的生理作用。由于特发性和LRRK 2相关的PD与蛋白质聚集体的神经元内积累有关，因此出现了一系列关键问题。首先，增加LRRK 2激酶活性的致病突变如何影响神经元中的溶酶体生物学？第二，突变诱导的溶酶体功能变化是否足以改变α-突触核蛋白的代谢？最后，致病突变引起的变化对LRRK 2激酶抑制剂逆转敏感吗？在这里，我们报告说，LRRK 2的突变诱导溶酶体形态和酸化的适度但显着的变化，并降低基础自噬流量相比，野生型神经元。这些变化与去污剂不溶性α-突触核蛋白的蓄积和α-突触核蛋白的神经元释放增加相关，并可通过LRRK 2激酶活性的药理学抑制逆转。这些数据证明了天然神经元LRRK 2激酶活性对溶酶体功能和α-突触核蛋白稳态的关键和疾病相关影响。此外，他们还表明，溶酶体功能障碍、神经元α-突触核蛋白代谢改变以及数十年来聚集蛋白的潜在积累可能导致这种迟发型家族性PD的发病机制。
Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson’s disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD.
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影响因子：
3.3
作者：
Caesar, M.;Felk, S.;Gillardon, F.
通讯作者：
Gillardon, F.
影响因子：
3.6
作者：
Cullen, Valerie;Lindfors, Maria;Ng, Juliana;Paetau, Anders;Swinton, Erika;Kolodziej, Piotr;Boston, Heather;Saftig, Paul;Woulfe, John;Feany, Mel B.;Myllykangas, Liisa;Schlossmacher, Michael G.;Tyynela, Jaana
通讯作者：
Tyynela, Jaana
影响因子：
4.7
作者：
Crabtree D;Dodson M;Ouyang X;Boyer-Guittaut M;Liang Q;Ballestas ME;Fineberg N;Zhang J
通讯作者：
Zhang J
DOI：
10.1016/j.bbrc.2009.08.163
发表时间：
2009-11-20
影响因子：
3.1
作者：
Greggio, Elisa;Taymans, Jean-Marc;Zhen, Eugene Yuejun;Ryder, John;Vancraenenbroeck, Renee;Beilina, Alexandra;Sun, Peng;Deng, Junpeng;Jaffe, Howard;Baekelandt, Veerle;Merchant, Kalpana;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ