The functional role of MAST1 in mediating a-synucleinopathies and related dementia

项目摘要 突触核蛋白病，包括路易体痴呆（DLB），其特征在于 错误折叠的α-突触核蛋白（α-syn）。痴呆是α-突触核蛋白病的常见症状：DLB是第二大 常见的痴呆后阿尔茨海默病（AD）占痴呆病例的30%;约30%的AD 病例还患有α-突触核蛋白病，导致比单独的AD更快和更严重的认知下降。 除了认知和记忆功能障碍，痴呆症患者还患有焦虑、抑郁和 情绪波动新出现的证据表明，致病性α-syn是一种朊病毒样蛋白， 病理在胃肠道中传播，导致神经变性和认知功能障碍。的 然而，病因不明，仍然缺乏有效的治疗方法，特别是对于α-syn肠-脑扩散 认知能力下降。 我们以前发现，铂，一种最广泛使用的化疗药物，用于各种类型的肿瘤， 癌症，诱导微管相关丝氨酸/苏氨酸激酶1（MAST 1）的表达， 在有丝分裂后神经元中高度表达的相关蛋白激酶。MAST 1在癌症中的诱导 细胞激活促存活信号传导并因此导致铂抗性和治疗失败。我们 注意到MAST 1水平在某些类型的癌症中升高，特别是在神经母细胞瘤细胞中， 一些神经元表型。有趣的是，MAST 1也被鉴定为AD相关基因， 患者我们的蛋白质阵列数据确定MAST 1为α-syn的潜在结合伴侣。我们一贯认为， 过表达MAST 1 WT而非激酶死亡突变体D497D促进α-syn S129磷酸化， α-突触核蛋白病的标志物因此，我们利用α-syn PFF，一个重要的模型系统， 使得研究错误折叠的α-syn在神经元之间的传递成为可能。PFF诱导聚集 内源性α-syn在原代皮层神经元中的表达，这可以通过MAST 1敲低来减少，这表明 MAST 1在发病机制中的重要作用。我们的中心假设是MAST 1可以驱动α-syn病理 通过直接磷酸化α-syn，神经元到神经元的扩散和痴呆。以MAST 1为目标可能代表 一种有前途的治疗β-突触核蛋白病和相关痴呆的策略。因此，我们建议 具体目的1：确定MAST 1在介导神经元- 致病性β-突触核蛋白向神经元的传递。具体目的2：评价MAST 1抑制剂在以下患者中的疗效： 抑制α-突触核蛋白病和相关痴呆。

PROJECT SUMMARY ‐Synucleinopathies, including dementia with Lewy bodies (DLB), are characterized by the accumulation of misfolded α‐synuclein (α‐syn). Dementia is a common symptom in α‐synucleinopathies: DLB is the 2nd most common dementia after Alzheimer's disease (AD) accounting for 30% of dementia cases; Around 30% of AD cases also suffer from α‐synucleinopathy resulting in a more rapid and severe cognition decline than AD alone. In addition to cognitive and memory dysfunction, patients with dementia also suffer from anxiety, depression and mood swings. Emerging evidence shows that pathogenic α‐syn is a prion-like protein that initiates the α‐syn pathology spread in the gastrointestinal tract, resulting in neurodegeneration and cognition dysfunction. The etiology, however, is unknown and effective therapies are still lacking, especially for α-syn gut-brain spreading and cognition decline. We previously uncovered that platinum, one of the most widely used chemotherapy drug for a variety types of cancer, induces expression of microtubule-associated serine/threonine kinase 1 (MAST1), a microtubule- associated protein kinase that is highly expressed in post-mitotic neurons. The induction of MAST1 in cancer cells activates pro-survival signaling and consequently leads to platinum resistance and treatment failure. We noticed that MAST1 level is elevated in certain types of cancer, particularly in neuroblastoma cells that show some neuronal phenotype. Interestingly, MAST1 has been also identified as an AD associated gene in AD patients. Our protein array data identified MAST1 as a potential binding partner for α-syn. Consistently, overexpressing MAST1 WT but not kinase-dead mutant D497D promoted α-syn S129 phosphorylation, a well- established marker for α-synucleinopathies. We therefore utilized α-syn PFF, an important model system that enables the study of the transmission of misfolded α-syn from neuron to neuron. PFF induced the aggregation of endogenous α-syn in primary cortical neurons which can be reduced by MAST1 knockdown, suggesting an important role of MAST1 in the pathogenesis. Our central hypothesis is that MAST1 can drive α-syn pathology neuron-to-neuron spreading and dementia by directly phosphorylating α-syn. Targeting MAST1 may represent a promising therapeutic strategy for -synucleinopathies and related dementia. Accordingly, we propose the following aims to test our hypothesis: Specific Aim 1: To determine the role of MAST1 in mediating the neuron- to-neuron transmission of pathogenic -synuclein. Specific Aim 2: To evaluate the efficacy of MAST1 inhibitor in suppressing α-synucleinopathies and related dementia.