Department of Neurology, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Parkinsonism Relat Disord. 2012 Aug;18(7):819-23. doi: 10.1016/j.parkreldis.2012.03.024. Epub 2012 Apr 22.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal-dominant familial Parkinson's disease (FPD). The variable pathological features of LRRK2-linked FPD include Lewy bodies, degeneration of anterior horn cells associated with axonal spheroids, neurofibrillary tangles (NFTs) and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusion bodies. Furthermore, abnormal hyperphosphorylation of microtubule associated protein tau, in part generated by catalysis of protein kinases, has been reported to be involved in progressive neurodegeneration in a number of diseases, including FPD. Thus, we examined six patients carrying the LRRK2 I2020T mutation, a pathogenic mutation associated with PARK8, and found abnormal tau phosphorylation depositions in the brainstem. Additionally, we found LRRK2 I2020T enhanced tau phosphorylation in cultured cells co-expressing LRRK2-I2020T and 3 or 4-repeated tau. This is the first report describing the relationship between hyperphosphorylation of tau and LRRK2 I2020T.
LRRK2 基因突变是常染色体显性家族性帕金森病（FPD）最常见的原因。LRRK2 相关 FPD 的可变病理特征包括路易体、与轴突球体相关的前角细胞变性、神经原纤维缠结（NFT）和 TAR DNA 结合蛋白 43 kDa（TDP-43）阳性包涵体。此外，微管相关蛋白 tau 的异常过度磷酸化，部分由蛋白激酶催化产生，据报道与包括 FPD 在内的多种疾病的进行性神经退行性变有关。因此，我们检查了 6 名携带 LRRK2 I2020T 突变的患者，该突变与 PARK8 相关，发现脑干中有异常 tau 磷酸化沉积。此外，我们发现共表达 LRRK2-I2020T 和 3 或 4 重复 tau 的培养细胞中 LRRK2 I2020T 增强了 tau 的磷酸化。这是首次描述 tau 的过度磷酸化与 LRRK2 I2020T 之间的关系。
