LRRK2 and ubiquitination: implications for kinase inhibitor therapy.
LRRK2 and ubiquitination: implications for kinase inhibitor therapy.
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DOI：
10.1042/bj20150785
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发表时间：
2015-09-15
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影响因子：
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通讯作者：
Melrose HL
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作者：
Melrose HL
LRRK 2（富含亮氨酸重复序列激酶2）中的致病性突变和风险变体代表了家族性和散发性PD（帕金森病）的最常见遗传原因。LRRK 2蛋白在整个脑和外周广泛表达。在结构上，LRRK 2含有几个功能结构域，包括由激酶和GT3结构域组成的双酶核心。疾病相关的变异体存在于这两个酶结构域以及COR [ROC的C-末端（复合蛋白的Ras）]和WD 40蛋白-蛋白结合结构域中。激酶结构域被广泛认为与毒性有关，因此制药工作的重点集中在开发LRRK 2激酶抑制剂上。然而，最近的数据表明，抑制LRRK 2活性导致LRRK 2水平降低和外周副作用，这与纯合LRRK 2敲除和LRRK 2激酶死亡啮齿动物模型中观察到的相似。在最近一期的《生物化学杂志》上，Nichols领导的一项研究表明，LRRK 2细胞磷酸化位点（Ser 910/Ser 935/Ser 955/Ser 973）的去磷酸化触发了其泛素化和随后的降解，因此可能导致在LRRK 2敲除/激酶死亡或经药物治疗的啮齿动物和灵长类动物的外周组织中观察到的功能表型丧失。尽管从激酶抑制剂的角度来看是负面的，但这些数据为LRRK 2生物学和治疗方法打开了新的途径，以抵消LRRK 2毒性。
Pathogenic mutations and risk variants in LRRK2 (leucine-rich repeat kinase 2) represent the most common genetic cause of familial and sporadic PD (Parkinson's disease). LRRK2 protein is widely expressed throughout the brain and the periphery. Structurally, LRRK2 contains several functional domains, including a dual enzymatic core consisting of a kinase and GTPase domain. Disease-linked variants are found in both these enzymatic domains as well as in the COR [C-terminal of ROC (Ras of complex proteins)] and WD40 protein–protein binding domain. The kinase domain is widely believed to be linked to toxicity, and thus the thrust of pharmaceutical effort has focused on developing LRRK2 kinase inhibitors. However, recent data have suggested that inhibition of LRRK2 activity results in reduced LRRK2 levels and peripheral side effects, which are similar to those observed in homozygous LRRK2-knockout and LRRK2 kinase-dead rodent models. In a recent issue of the Biochemical Journal, a study led by Nichols reveals that dephosphorylation of LRRK2 cellular phosphorylation sites (Ser910/Ser935/Ser955/Ser973) triggers its ubiquitination and subsequent degradation and thus may account for the loss of function phenotypes observed in peripheral tissues in LRRK2-knockout/kinase-dead or inhibitor-treated rodents and primates. Albeit negative from a kinase inhibitor standpoint, the data open new avenues for LRRK2 biology and therapeutic approaches to counteract LRRK2 toxicity.