Regulation of synaptic protein phosphorylation by kinases plays a critical role in synaptic development and synaptic transmission. Yet, despite the identification of over 500 protein kinases in the human genome, our current knowledge of the kinases located in the synapse and mechanisms underlying their regulation of synaptic structure and neurotransmission in vivo are quite limited. The goal of this project is to elucidate the role f the evolutionarily conserved DYRK1A/MNB kinase in regulating synaptic structure and function, using Drosophila as a model system. DYRK1A/MNB is located in the Down syndrome critical region on chromosome 21, upregulated in Down syndrome, and a strong candidate gene for mental retardation and locomotor deficits in Down syndrome. Understanding DYRK1A/MNB function will thus shed light on fundamental mechanisms underlying neuronal function in health and disease. Our preliminary results show that DYRK1A/MNB is enriched in the neuromuscular junction, and DYRK1A/MNB hypomorphic mutations have profound effects on synaptic morphology and endocytosis. We found that DYRK1A/MNB phosphorylates and affects the activity of synaptojanin, a phosphoinositol phosphatase important for endocytosis. This has led to our central hypothesis that DYRK1A/MNB plays a critical role in regulating synaptic structure and synaptic vesicle recycling. In this proposal, we will take an integrated approach combining genetics, biochemical, and cell biological and electrophysiological analyses to address the following questions: 1) what are the effects of DYRK1A/MNB dosage imbalance on synaptic morphology and function? 2) What is the spatiotemporal requirement of DYRK1A/MNB in regulating synaptic morphology and function? 3) Does DYRK1A/mnb regulate synaptic transmission through phosphorylation of synaptojanin? 4) What are mechanisms underlying DYRK1A/MNB induced changes in synaptic growth? Accomplishing these goals will lay an important foundation for future studies identifying new protein targets and signaling mechanisms that affect synaptic function. As defective synaptic transmission is associated with a number of neurological disorders and DYRK1A is implicated in Down syndrome, information obtained from this study will help to understand the molecular basis of synaptic dysfunction in these diseases and help to contribute to therapeutic development in the future.
The goal of the proposed study is to better understand the role of a protein that has been implicated in Down syndrome and how it regulates communication between neurons. Completion of the proposed study will ultimately help to understand and treat a number of neurological diseases that are associated with defective synaptic function, including Alzheimer's, Parkinson's and Down syndrome.
|Chen, Chun-Kan; Bregere, Catherine; Paluch, Jeremy et al. (2014) Activity-dependent facilitation of Synaptojanin and synaptic vesicle recycling by the Minibrain kinase. Nat Commun 5:4246|
|Shaw, Jillian L; Chang, Karen T (2013) Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3* signaling. PLoS Genet 9:e1003792|