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

项目总结

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.