SYNJ1 Mediates a Novel Signaling Pathway in Parkinson's Disease

 描述（由申请人提供）：我们项目的目标是基于遗传形式的帕金森病（PD）研究潜在的致病机制。我们和另外两个研究小组已经在染色体21 q22上的SYNJ 1基因中发现了与早发性帕金森综合征相关的相同突变。作为脑中最重要的肌醇磷酸酶之一，synaptojanin 1（由SYNJ 1编码）参与膜运输的许多方面，并与包括阿尔茨海默病和唐氏综合征在内的许多脑疾病有关。然而，其在PD中的致病机制尚未研究。新出现的证据揭示了α-突触核蛋白、LRRK 2和其他PD相关基因在PD早期解除突触囊泡（SV）循环调节的致病途径的会聚。我们的初步研究表明，在SYNJ 1杂合子小鼠和LRRK 2-G2019 S小鼠中SV内吞和多巴胺能传递具有共同的表型。SYNJ 1杂合子小鼠在黑质中选择性地形成异常树突状形态和脂质组成。鉴于synaptojanin 1与内亲素A形成蛋白复合物，内亲素A被鉴定为推定的LRRK 2底物，我们提出了一个“LRRK 2-内亲素A-synaptojanin 1”信号传导轴用于调节SV循环，其在PD中被解除调节。我们将使用最先进的光学工具和遗传动物模型来验证这一假设。我们项目的完成有望为PD的致病机制提供深入了解，并为识别新的治疗方法开辟新的途径。

 DESCRIPTION (provided by applicant): The goal of our project is to investigate pathogenic mechanism underlying Parkinson's disease (PD) based on inherited forms of PD. We and two other groups have identified the same mutation in SYNJ1 gene on chromosome 21q22 that is associated with early onset Parkinsonism. As one of the most important inositol phosphatases in the brain, synaptojanin1 (encoded by SYNJ1) is involved in many aspects of membrane trafficking and has been implicated in a number of brain disorders including Alzheimer's disease and Down's syndrome. However, its pathogenic mechanism in PD has not been studied. Emerging evidence reveals the convergence of pathogenic pathways for α-synuclein, LRRK2 and other PD-related genes in deregulating synaptic vesicle (SV) cycling in the early stage of PD. Our preliminary study shows shared phenotypes in SV endocytosis and dopaminergic transmission in SYNJ1 heterozygous mice and LRRK2-G2019S mice. SYNJ1 heterozygous mice develop abnormal dendritic morphology and lipid composition selectively in substantia nigra. Given that synaptojanin1 forms a protein complex with endophilin A, which was identified as a putative LRRK2 substrate, we propose a "LRRK2-endophilinA-synaptojanin1" signaling axis for the regulation of SV cycling, which is deregulated in PD. We will test the hypothesis using state-of-art optical tools and genetic animal models. Completion of our project is expected to provide insight into the pathogenic mechanism for PD and open new avenues for identification of novel therapeutics.