Instituto de Medicina Molecular, 1649-028, Lisbon, Portugal.
Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany.
Mol Neurobiol. 2016 Jul;53(5):3124-3135. doi: 10.1007/s12035-015-9209-z. Epub 2015 May 27.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer's disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2-mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD.
LRRK2 基因中的亮氨酸丰富重复激酶 2（LRRK2）突变是家族性帕金森病（PD）最常见的原因，但也存在于散发性病例中。G2019S-LRRK2 突变位于蛋白质的激酶结构域，并且一直被报道促进激酶功能的获得。已经报道了几种作为 LRRK2 底物和/或相互作用物的蛋白质，这表明 PD 中神经退行性变可能涉及的途径。过度磷酸化的 Tau 蛋白在神经原纤维缠结中积累，这是阿尔茨海默病和额颞叶痴呆的典型病理标志。此外，它也经常在 PD 患者的大脑中发现。尽管 LRRK2 是一种激酶，但似乎与 Tau 的假定相互作用与磷酸化无关。然而，这种相互作用的潜在机制和细胞后果仍不清楚。在这项研究中，我们证明了 LRRK2 与 Tau 之间的相互作用，并且 LRRK2 促进非单体和高分子量（HMW）Tau 物种的积累，而不依赖于其激酶活性。有趣的是，我们发现 LRRK2 增加了 Tau 的分泌，这可能是由于 Tau 蛋白酶体降解的损害。我们的数据强调了 LRRK2 调节细胞内 Tau 水平的机制，有助于由 LRRK2 介导的蛋白酶体损伤引起的病理进展。总的来说，我们的发现表明 LRRK2 和蛋白酶体活性之间的相互作用可能是 PD 治疗干预的一个有效靶点。
