The roles of microtubule-associated serine/threonine kinase-1 in regulating neuronal development

About This Grant

Abstract: Neurodevelopmental disorders associated with autism, intellectual disability, and cortical malformations are frequently caused by rare genetic abnormalities. Recently rare de-novo mutations in MAST1 have been identified in multiple patients with severe intellectual disability and cortical malformations. MAST1 is a microtubule- associated serine/threonine protein kinase-1 that is specifically expressed in neurons during brain development. However, little is known about the roles of MAST1 in regulating neuronal properties, and how MAST1 mutations affect the cellular and molecular mechanisms to cause neurodevelopmental deficits. The goal of this project is to elucidate the role of MAST1 in regulating neurodevelopment under normal conditions and disease states. In our preliminary experiments, we generated telencephalic brain organoids and neurons from control as well as patient and engineered stem cells with MAST1 mutations. We found microcephaly-associated size deficits in MAST1-mutated organoids due to reduced number of neurons and smaller neuropil size. We also observed elevated apoptosis, impaired neurites, and mitochondrial abnormalities in MAST1 mutated cortical neurons as compared to control neurons. We hypothesize that MAST1 regulates mitochondria trafficking in neurites and that mutated MAST1 causes neurite outgrowth deficits by disrupting mitochondria transport, ATP synthesis, and interactions with its binding partners. Collectively, these deficits lead to hyperactive mitochondria, overproduction of reactive oxygen species, neuronal apoptosis, and microcephaly-associated deficits in MAST1-mutated organoids. We will test this hypothesis in the following Specific Aims: (1) We will perform live-cell imaging on control and MAST1-mutated neurons to characterize mitochondria trafficking and ATP synthesis in axons and dendrites. (2) We will conduct structural-functional studies to determine how MAST1 interacts with mitochondria in neurons. Finally, (3) we will investigate how patient MAST1 mutations affect MAST1 interaction with its binding partners. The proposed research is significant because it is expected to substantially advance understanding of the cellular and molecular mechanisms disrupted in patient with neurodevelopmental disorders caused by MAST1 mutations and other brain disorders associated with mitochondrial abnormalities.