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

项目总结 -突触核苷酸病，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-突触核病的常见症状：痴呆症排在第二位 阿尔茨海默病(AD)后常见痴呆症占痴呆病例的30%；约占AD的30% 2例患者还患有α-突触核素病，导致的认知能力下降比单纯AD更快、更严重。 除认知和记忆功能障碍外，痴呆症患者还患有焦虑、抑郁和 情绪波动。新的证据表明致病的α-SYN是一种启动α-SYN的类病毒蛋白 病理扩散到胃肠道，导致神经变性和认知功能障碍。这个 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肠脑播散。 认知能力下降。 我们之前发现，铂是治疗各种类型肺癌最广泛使用的化疗药物之一 诱导微管相关丝氨酸/苏氨酸激酶1(MAST1)的表达，这是一种微管- 相关蛋白激酶，在有丝分裂后神经元中高表达。MAST1基因在肿瘤中的诱导 细胞激活促生存信号，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 一些神经元表型。有趣的是，MAST1也被认为是AD的相关基因 病人。我们的蛋白质阵列数据表明，MAST1是α-SYN的潜在结合伙伴。始终如一， 过表达MAST1WT而不是激酶死亡突变体D497D促进了α-SYN S129的磷酸化，这是一个很好的 建立了α-突触核病症的标志物。因此，我们使用了α-SYN PFF，这是一个重要的模型系统 能够研究错误折叠的α-SYN从神经元到神经元的传递。PFF诱导的聚集 在原代皮质神经元中内源性α-SYN的表达可被MAST1基因敲除而减少，提示 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 通过直接磷酸化α-SYN实现神经元到神经元的扩散和痴呆。以MAST1为目标可能代表 一种有前景的治疗-突触核病症和相关痴呆的策略。因此，我们建议 以下旨在验证我们的假设：具体目标1：确定MAST1在调节神经元- 致病-突触核蛋白向神经元的传递。特异目的2：评价MAST1抑制剂对人卵巢癌的疗效 抑制α-突触核糖核病和相关痴呆。

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.