LRRK2 activation in idiopathic Parkinson's disease.
LRRK2 activation in idiopathic Parkinson's disease.
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DOI：
10.1126/scitranslmed.aar5429
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发表时间：
2018-07-25
影响因子：
17.1
通讯作者：
Greenamyre JT
中科院分区：
文献类型：
--
作者：
Di Maio R;Hoffman EK;Rocha EM;Keeney MT;Sanders LH;De Miranda BR;Zharikov A;Van Laar A;Stepan AF;Lanz TA;Kofler JK;Burton EA;Alessi DR;Hastings TG;Greenamyre JT
由于富含亮氨酸的重复序列激酶2（LRRK 2）基因突变导致的激酶活性异常增加是帕金森病（PD）的原因，约3-4%的帕金森病患者患有这种疾病。我们现在发现，在特发性PD患者的大脑中，通过涉及α-突触核蛋白和线粒体损伤的氧化机制，LRRK 2激酶活性在脆弱的多巴胺神经元中异常增加，这导致了内溶酶体功能障碍和磷酸化α-突触核蛋白的积累。因此，独立于突变，LRRK 2激酶活性的激活对发病机制有重要贡献，表明LRRK 2激酶活性的抑制将对大多数PD患者有用。富亮氨酸重复序列激酶2（LRRK 2）的错义突变导致家族性帕金森病（PD）;然而，野生型LRRK 2在特发性PD（iPD）中的作用尚不清楚。在这里，我们表明，野生型LRRK 2激酶活性选择性增强黑质多巴胺神经元在特发性PD和两种不同的动物模型的疾病。这通过ROS信号传导发生，导致LRRK 2底物Rab 10的磷酸化和其他下游后果，包括线粒体蛋白输入和溶酶体功能的异常。总体而言，我们的工作表明，独立于突变，野生型LRRK 2在特发性PD中起着关键作用。因此，LRRK 2导向疗法可能对大多数PD患者有用。
Abnormally increased kinase activity due to mutations in the leucine rich repeat kinase 2 (LRRK2) gene is the cause of Parkinson disease (PD) in about 3–4% of people with the disease. We now show that, in the brains of individuals with idiopathic PD, LRRK2 kinase activity is aberrantly increased in vulnerable dopamine neurons by oxidative mechanisms involving α-synuclein and mitochondrial impairment – and this causes endolysosomal dysfunction and accumulation of phosphorylated α-synuclein. Thus, independent of mutation, activation of LRRK2 kinase activity contributes importantly to pathogenesis, suggesting inhibition of LRRK2 kinase activity will be useful for the majority of PD patients. Missense mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson disease (PD); however, the role of wildtype LRRK2 in idiopathic PD (iPD) is unclear. Here, we show that wildtype LRRK2 kinase activity is selectively enhanced in substantia nigra dopamine neurons in idiopathic PD and two different animal models of the disease. This occurs through ROS signaling, resulting in phosphorylation of the LRRK2 substrate Rab10 and other downstream consequences including abnormalities of mitochondrial protein import and lysosomal function. Overall, our work shows that, independent of mutations, wildtype LRRK2 plays a key role in idiopathic PD. LRRK2-directed therapeutics may therefore be useful for most people with PD.
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DOI：
10.1523/jneurosci.5601-11.2012
发表时间：
2012-02-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Moehle MS;Webber PJ;Tse T;Sukar N;Standaert DG;DeSilva TM;Cowell RM;West AB
通讯作者：
West AB
影响因子：
4.8
作者：
Daher, Joao P. L.;Abdelmotilib, Hisham A.;West, Andrew B.
通讯作者：
West, Andrew B.
影响因子：
8.6
作者：
Fraser, Kyle B.;Rawlins, Ashlee B.;Clark, Rachel G.;Alcalay, Roy N.;Standaert, David G.;Liu, Nianjun;West, Andrew B.
通讯作者：
West, Andrew B.
影响因子：
6.1
作者：
Greggio, Elisa;Jain, Shushant;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
16.2
作者：
Paisán-Ruíz, C;Jain, S;Singleton, AB
通讯作者：
Singleton, AB