Following neurotransmitter release, synaptic vesicle membrane and protein components are rapidly retrieved from the plasma membrane through endocytosis, and functional synaptic vesicles are subsequently regenerated from the endocytosed components. This fundamental process, called synaptic vesicle recycling, is crucial for sustaining neuronal communication across a wide range of neuronal activities. Impaired synaptic vesicle recycling can thus deleteriously affect neuronal survival and function, and is associated with numerous neurological disorders. There are multiple modes of synaptic vesicle endocytosis, including clathrin-mediated endocytosis and clathrin-independent bulk endocytosis. While it is widely known that dynamic phosphorylation of synaptic proteins by kinases delicately regulates clathrin-mediated endocytosis, mechanisms modulating clathrin-independent bulk endocytosis are not well understood. In this proposal, will use Drosophila melanogaster, which offers the advantage of powerful genetics and well-characterized glutamatergic synapses at the neuromuscular junction, to investigate the functions of a synaptic kinase called Minibrain (MNB), also known as DYRK1A, in regulating multiple steps of synaptic vesicle recycling. We will take a multidisciplinary approach combining genetics, biochemistry, cell biology, and electrophysiological analyses to address the role of MNB/DYRK1A in clathrin-independent bulk endocytosis and synaptic vesicle regeneration. We will address the following questions in this proposal: 1) what is the role of MNB/.DYRK1A in regulating clathrin-independent bulk endocytosis? 2) Does MNB regulate bulk endocytosis through phosphorylation of Synaptojanin, a previously identified synaptic target of MNB? 3) Is MNB required for the recovery of functional synaptic vesicles pools? 4) What is the mechanism by which MNB regulates functional recovery of synaptic vesicles? As MNB/DYRK1A is upregulated in Down syndrome and mutated in some cases of Autism, a thorough understanding of MNB functions at the synapse will provide novel insights into mechanisms underlying neurological disorders and contribute to therapeutic development in the future.
The goal of the proposed study is to better understand how a protein perturbed in Down syndrome and Autism spectrum disorder regulates efficient communication between neurons. Completion of the proposed study will ultimately help to understand and to treat a number of neurological diseases that are associated with defective synaptic functions.
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