White Linda R, Toft Mathias, Kvam Sylvia N, Farrer Matthew J, Aasly Jan O
Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
J Neurosci Res. 2007 May 1;85(6):1288-94. doi: 10.1002/jnr.21240.
The 6055G>A mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in a G2019S substitution in the mixed-lineage kinase domain of Lrrk2, causing autosomal dominant Parkinson's disease (PD). We hypothesized the mutation alters cellular mitogen-activated protein kinase (MAPK) signalling cascades, and might be detectable in tissues other than in the brain. We therefore compared total levels and activation of the signalling proteins Src, HSP27, p38 MAPK, JNK, and ERK, in extracts of leukocytes isolated from patients with PD carrying the G2019S mutation, healthy mutation carriers, patients with idiopathic PD, and healthy controls. Phosphorylation of Src, HSP27, and JNK was reduced significantly in cell extracts from patients with G2019S-associated PD compared to healthy controls. Similarly, phosphorylation was reduced significantly in Src and HSP27 in the group of healthy carriers of the mutation, as well as in patients with idiopathic PD. Significant reductions in total Src were also observed in these three groups compared to the controls. The results of this pilot project therefore indicate significant alterations in key signalling proteins in leukocytes from patients with PD, and were most pronounced in G2019S-associated PD. Changes in MAPK-signalling may thus be common to PD pathophysiology, regardless of aetiology. Such changes may also be shown in blood samples during the preclinical stage of LRRK2-associated PD, which could be particularly important for the development of neuroprotective strategies to delay onset, or slow progression of PD.
富含亮氨酸重复激酶2（LRRK2）基因中的6055G>A突变导致Lrrk2的混合谱系激酶结构域中发生G2019S替代，引发常染色体显性帕金森病（PD）。我们推测该突变会改变细胞丝裂原活化蛋白激酶（MAPK）信号级联反应，并且可能在脑组织以外的其他组织中被检测到。因此，我们比较了从携带G2019S突变的PD患者、健康突变携带者、特发性PD患者以及健康对照者中分离出的白细胞提取物中信号蛋白Src、HSP27、p38 MAPK、JNK和ERK的总水平及活化情况。与健康对照相比，G2019S相关PD患者细胞提取物中Src、HSP27和JNK的磷酸化水平显著降低。同样，在突变的健康携带者组以及特发性PD患者中，Src和HSP27的磷酸化水平也显著降低。与对照组相比，这三组中Src的总量也显著减少。因此，这个初步项目的结果表明，PD患者白细胞中的关键信号蛋白存在显著改变，在G2019S相关PD中最为明显。MAPK信号传导的变化可能是PD病理生理学的共同特征，无论其病因如何。这种变化在LRRK2相关PD的临床前期血样中可能也会出现，这对于开发延缓PD发病或减缓其进展的神经保护策略可能尤为重要。
