LRRK2 at Striatal Synapses: Cell-Type Specificity and Mechanistic Insights.
LRRK2 at Striatal Synapses: Cell-Type Specificity and Mechanistic Insights.
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DOI：
10.3390/cells11010169
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发表时间：
2022-01-05
期刊：
影响因子：
6
通讯作者：
Parisiadou L
中科院分区：
文献类型：
--
作者：
Skelton PD;Tokars V;Parisiadou L
富含亮氨酸重复激酶 2 (LRRK2) 的突变会导致帕金森病，其临床表现和进展与特发性帕金森病相似，并且常见的变异与疾病风险相关。啮齿动物模型中基因型的重演会导致多巴胺释放异常，并增加多巴胺能神经元对损伤的敏感性，使 LRRK2 成为了解帕金森病病理学的有价值的模型。它也是一个有前途的药物靶标，目前正在开发靶向疗法。大脑中 LRRK2 mRNA 和蛋白质的表达在不同区域和细胞特性之间存在很大差异。越来越多的研究表明，致病性 LRRK2 突变会在明显的神经变性发生之前破坏纹状体突触。 LRRK2 的几种底物和相互作用物已被鉴定出可能以细胞类型特异性的方式介导这些前神经退行性变化。本综述讨论了致病性 LRRK2 突变对纹状体神经元的影响，包括细胞类型特异性和通路特异性改变。它还强调了一些可以介导纹状体功能改变的 LRRK2 效应子，包括 Rab 和蛋白激酶 A。通过提高我们对纹状体神经元中 LRRK2 突变致病作用的理解而获得的经验教训将适用于剖析多巴胺能神经元转录多样化亚型中 LRRK2 功能的细胞类型特异性，也可增加我们对 基底神经节发育和生物学。最后，它将为帕金森病治疗方法的开发提供信息。
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease with a similar clinical presentation and progression to idiopathic Parkinson’s disease, and common variation is linked to disease risk. Recapitulation of the genotype in rodent models causes abnormal dopamine release and increases the susceptibility of dopaminergic neurons to insults, making LRRK2 a valuable model for understanding the pathobiology of Parkinson’s disease. It is also a promising druggable target with targeted therapies currently in development. LRRK2 mRNA and protein expression in the brain is highly variable across regions and cellular identities. A growing body of work has demonstrated that pathogenic LRRK2 mutations disrupt striatal synapses before the onset of overt neurodegeneration. Several substrates and interactors of LRRK2 have been identified to potentially mediate these pre-neurodegenerative changes in a cell-type-specific manner. This review discusses the effects of pathogenic LRRK2 mutations in striatal neurons, including cell-type-specific and pathway-specific alterations. It also highlights several LRRK2 effectors that could mediate the alterations to striatal function, including Rabs and protein kinase A. The lessons learned from improving our understanding of the pathogenic effects of LRRK2 mutations in striatal neurons will be applicable to both dissecting the cell-type specificity of LRRK2 function in the transcriptionally diverse subtypes of dopaminergic neurons and also increasing our understanding of basal ganglia development and biology. Finally, it will inform the development of therapeutics for Parkinson’s disease.
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影响因子：
11.2
作者：
Biskup, Saskia;Moore, Darren J.;Dawson, Valina L.
通讯作者：
Dawson, Valina L.
影响因子：
3.5
作者：
Biosa, Alice;Trancikova, Alzbeta;Moore, Darren J.
通讯作者：
Moore, Darren J.
影响因子：
11.4
作者：
Cho, Hyun Jin;Yu, Jia;Cai, Huaibin
通讯作者：
Cai, Huaibin
DOI：
10.1523/jneurosci.4357-09.2009
发表时间：
2009-12-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andres-Mateos E;Mejias R;Sasaki M;Li X;Lin BM;Biskup S;Zhang L;Banerjee R;Thomas B;Yang L;Liu G;Beal MF;Huso DL;Dawson TM;Dawson VL
通讯作者：
Dawson VL
影响因子：
5.3
作者：
Beccano-Kelly DA;Kuhlmann N;Tatarnikov I;Volta M;Munsie LN;Chou P;Cao LP;Han H;Tapia L;Farrer MJ;Milnerwood AJ
通讯作者：
Milnerwood AJ