Turku Bioscience, University of Turku and Åbo Akademi University, Turku, Finland.
Department of Immunotechnology, Lund University, Lund, Sweden.
FASEB J. 2020 Nov;34(11):14217-14233. doi: 10.1096/fj.202001046R. Epub 2020 Sep 14.
Gain of function LRRK2-G2019S is the most frequent mutation found in familial and sporadic Parkinson's disease. It is expected therefore that understanding the cellular function of LRRK2 will provide insight on the pathological mechanism not only of inherited Parkinson's, but also of sporadic Parkinson's, the more common form. Here, we show that constitutive LRRK2 activity controls nascent protein synthesis in rodent neurons. Specifically, pharmacological inhibition of LRRK2, Lrrk2 knockdown or Lrrk2 knockout, all lead to increased translation. In the rotenone model for sporadic Parkinson's, LRRK2 activity increases, dopaminergic neuron translation decreases, and the neurites atrophy. All are prevented by LRRK2 inhibitors. Moreover, in striatum and substantia nigra of rotenone treated rats, phosphorylation changes are observed on eIF2α-S52(↑), eIF2s2-S2(↓), and eEF2-T57(↑) in directions that signify protein synthesis arrest. Significantly, translation is reduced by 40% in fibroblasts from Parkinson's patients (G2019S and sporadic cases alike) and this is reversed upon LRRK2 inhibitor treatment. In cells from multiple system atrophy patients, translation is unchanged suggesting that repression of translation is specific to Parkinson's disease. These findings indicate that repression of translation is a proximal function of LRRK2 in Parkinson's pathology.
LRRK2-G2019S 的功能获得性突变是家族性和散发性帕金森病中最常见的突变。因此，预计了解 LRRK2 的细胞功能不仅将为遗传性帕金森病的病理机制提供深入了解，也将为更为常见的散发性帕金森病提供深入了解。在这里，我们表明组成性 LRRK2 活性控制着啮齿动物神经元中新生蛋白的合成。具体而言，LRRK2 的药理学抑制、Lrrk2 敲低或 Lrrk2 敲除，都会导致翻译增加。在散发性帕金森病的鱼藤酮模型中，LRRK2 活性增加，多巴胺能神经元翻译减少，神经突萎缩。所有这些都可以被 LRRK2 抑制剂预防。此外，在鱼藤酮处理的大鼠纹状体和黑质中，观察到 eIF2α-S52（↑）、eIF2s2-S2（↓）和 eEF2-T57（↑）上的磷酸化变化，这些变化表明蛋白质合成被阻断。重要的是，帕金森病患者（G2019S 和散发性病例）的成纤维细胞中的翻译减少了 40%，而 LRRK2 抑制剂治疗后则逆转了这一现象。在多系统萎缩症患者的细胞中，翻译没有变化，这表明翻译的抑制是帕金森病特有的。这些发现表明，翻译的抑制是 LRRK2 在帕金森病病理中的一个近端功能。
