Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, UK.
Neurobiol Dis. 2013 Oct;58:183-90. doi: 10.1016/j.nbd.2013.05.017. Epub 2013 Jun 5.
Mutations in LRRK2 are the most common genetic cause of Parkinson's disease (PD). The most prevalent LRRK2 mutation is the G2019S coding change, located in the kinase domain of this complex multi-domain protein. The majority of G2019S autopsy cases feature typical Lewy Body pathology with a clinical phenotype almost indistinguishable from idiopathic PD (iPD). Here we have investigated the biochemical characteristics of α-synuclein in G2019S LRRK2 PD post-mortem material, in comparison to pathology-matched iPD. Immunohistochemistry with pS129 α-synuclein antibody showed that the medulla is heavily affected with pathology in G2019S PD whilst the basal ganglia (BG), limbic and frontal cortical regions demonstrated comparable pathology scores between G2019S PD and iPD. Significantly lower levels of the highly aggregated α-synuclein species in urea-SDS fractions were observed in G2019S cases compared to iPD in the BG and limbic cortex. Our data, albeit from a small number of cases, highlight a difference in the biochemical properties of aggregated α-synuclein in G2019S linked PD compared to iPD, despite a similar histopathological presentation. This divergence in solubility is most notable in the basal ganglia, a region that is affected preclinically and is damaged before overt dopaminergic cell death.
LRRK2 突变是帕金森病 (PD) 的最常见遗传原因。最常见的 LRRK2 突变是 G2019S 编码变化，位于该复杂多结构域蛋白的激酶结构域中。大多数 G2019S 尸检病例具有典型的路易体病理学特征，其临床表型与特发性 PD (iPD) 几乎无法区分。在这里，我们研究了 G2019S LRRK2 PD 死后组织中 α-突触核蛋白的生化特征，与病理学匹配的 iPD 进行了比较。用 pS129 α-突触核蛋白抗体进行免疫组织化学染色显示，G2019S PD 的髓质受到严重影响，而基底节 (BG)、边缘和额皮质区域的病理学评分在 G2019S PD 和 iPD 之间具有可比性。与 iPD 相比，BG 和边缘皮质中的 G2019S 病例中尿素-SDS 级分中高度聚集的 α-突触核蛋白的水平显著降低。尽管病例数量较少，但我们的数据突出表明，与 iPD 相比，G2019S 相关 PD 中聚集的 α-突触核蛋白的生化特性存在差异，尽管其组织病理学表现相似。这种溶解度的差异在基底节最为明显，基底节是一个在临床前受到影响并在多巴胺能细胞死亡之前受损的区域。
