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

MAST1 在介导 α-突触核蛋白病和相关痴呆中的功能作用

• 批准号: 10285549
• 负责人: Lingtao Jin
• 金额: $ 40.09万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285549
• 关键词: Accounting; Alzheimer' s Disease; Alzheimer' s disease patient; Anxiety; Automobile Driving; Binding; Biological Models; Biology; Brain; Brain region; Cells; Clinical Trials; Cognition; Cognitive; Collaborations; Data; Dementia; Dementia with Lewy Bodies; Development; Etiology; Functional disorder; Gastrointestinal tract structure; Genes; Goals; Hand; Human; Impaired cognition; In Vitro; Mediating; Memory impairment; Mental Depression; Microtubule-Associated Proteins; Microtubules; Mitotic; Modeling; Molecular; Moods; Mus; Nerve Degeneration; Neurologic Deficit; Neurons; Pathogenesis; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Platinum; Play; Protein Array; Protein Array Analysis; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Proxy; Resistance; Role; Signal Transduction; Testing; Therapeutic; Treatment Failure; Validation; alpha synuclein; behavior test; cancer cell; cancer type; chemotherapy; common symptom; drug repurposing; effective therapy; efficacy evaluation; improved; in vivo; inhibitor/antagonist; insight; knock-down; loss of function; mouse model; mutant; neurobehavioral; neuroblastoma cell; neurotoxicity; novel; overexpression; pre-clinical; preclinical study; prevent; prion-like; small molecular inhibitor; success; synuclein; synucleinopathy; targeted treatment; therapeutically effective; transmission process

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.

项目概要 α-突触核蛋白病，包括路易体痴呆 (DLB)，其特征是 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 是第二大症状 阿尔茨海默病（AD）之后的常见痴呆症占痴呆病例的 30%；大约30%的AD 病例还患有 α-突触核蛋白病，导致比单纯 AD 更快、更严重的认知能力下降。 痴呆症患者除了认知和记忆功能障碍外，还患有焦虑、抑郁等症状。 情绪波动。新出现的证据表明致病性 α-syn 是一种类似朊病毒的蛋白，可启动 α-syn 病理在胃肠道扩散，导致神经变性和认知功能障碍。这 然而，病因尚不清楚，仍然缺乏有效的治疗方法，特别是对于 α-syn 肠脑扩散 和认知能力下降。 我们之前发现铂是多种类型中使用最广泛的化疗药物之一 癌症，诱导微管相关丝氨酸/苏氨酸激酶 1 (MAST1) 的表达，微管相关丝氨酸/苏氨酸激酶 1 相关蛋白激酶在有丝分裂后神经元中高表达。 MAST1 在癌症中的诱导 细胞激活促生存信号传导，从而导致铂耐药和治疗失败。我们 注意到 MAST1 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，显示 一些神经元表型。有趣的是，MAST1也被鉴定为AD中的AD相关基因 患者。我们的蛋白质阵列数据将 MAST1 确定为 α-syn 的潜在结合伴侣。一贯地， 过表达 MAST1 WT 但不是激酶死亡突变体 D497D 促进 α-syn S129 磷酸化，这是一种良好的 建立了α-突触核蛋白病标记物。因此，我们利用了 α-syn PFF，这是一个重要的模型系统， 使得能够研究错误折叠的α-syn在神经元之间的传递。 PFF诱导聚集 原代皮质神经元中内源性 α-syn 的表达可通过 MAST1 敲低来减少，这表明 MAST1 在发病机制中的重要作用。我们的中心假设是 MAST1 可以驱动 α-syn 病理学 通过直接磷酸化 α-syn 来实现神经元间传播和痴呆。靶向 MAST1 可能代表 α-突触核蛋白病和相关痴呆症的一种有前景的治疗策略。据此，我们建议 以下目的是为了检验我们的假设： 具体目标 1：确定 MAST1 在介导神经元中的作用 致病性α-突触核蛋白向神经元的传递。具体目标 2：评估 MAST1 抑制剂在 抑制 α-突触核蛋白病和相关痴呆。