Parkinson’s disease (PD), Alzheimer’s disease (AD) and Amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases hallmarked by the formation of toxic protein aggregates. However, targeting these aggregates therapeutically have thus far shown no success. The treatment of AD has remained particularly problematic since no new drugs have been approved in the last 15 years. Therefore, novel therapeutic targets need to be identified and explored. Here, through the integration of genomic and proteomic data, a set of proteins with strong links to α-synuclein-aggregating neurodegenerative diseases was identified. We propose 17 protein targets that are likely implicated in neurodegeneration and could serve as potential targets. The human phosphatidylinositol 5-phosphatase synaptojanin-1, which has already been independently confirmed to be implicated in Parkinson’s and Alzheimer’s disease, was among those identified. Despite its involvement in PD and AD, structural aspects are currently missing at the molecular level. We present the first atomistic model of the 5-phosphatase domain of synaptojanin-1 and its binding to its substrate phosphatidylinositol 4,5-bisphosphate (PIP₂). We determine structural information on the active site including membrane-embedded molecular dynamics simulations. Deficiency of charge within the active site of the protein is observed, which suggests that a second divalent cation is required to complete dephosphorylation of the substrate. The findings in this work shed light on the protein’s binding to phosphatidylinositol 4,5-bisphosphate (PIP₂) and give additional insight for future targeting of the protein active site, which might be of interest in neurodegenerative diseases where synaptojanin-1 is overexpressed.

帕金森氏病（PD），阿尔茨海默氏病（AD）和肌萎缩性侧索硬化症（ALS）是神经退行性疾病，其特征在于有毒蛋白质聚集体的形成。然而，迄今为止，在治疗上靶向这些聚集体并未显示出成功。由于在过去的15年中没有新的药物被批准，因此AD的治疗仍然存在特别的问题。因此，需要确定和探索新的治疗靶标。在这里，通过基因组和蛋白质组学数据的整合，鉴定出了一组与α-突触核蛋白聚集性神经退行性疾病有密切联系的蛋白质。我们提出了17种蛋白质靶标，这些靶标可能与神经退行性变有关，可以作为潜在靶标。人类磷脂酰肌醇5-磷酸酶突触素-1，其中已独立鉴定出与帕金森氏病和阿尔茨海默氏病有关。尽管它参与了PD和AD，但在分子水平上目前缺少结构方面。我们提出了突触神经素-1的5-磷酸酶结构域的第一个原子模型及其与其底物磷脂酰肌醇4,5-二磷酸（PIP）的结合₂）。我们确定活动位置上的结构信息，包括膜嵌入的分子动力学模拟。观察到蛋白质活性位点内的电荷不足，这表明需要第二个二价阳离子来完成底物的去磷酸化。这项工作的发现揭示了该蛋白与磷脂酰肌醇4,5-双磷酸酯（PIP ₂）的结合，并为将来靶向该蛋白的活性位点提供了更多的见识，这可能是突触核蛋白-1过表达的神经退行性疾病的关注点。