Ravi Muddashetty

Ravi MuddashettyActivity mediated protein synthesis in neurons-Mechanism and impact

Protein synthesis is decentralized in neurons and is spatio-temporally linked to neuronal activity. Locally synthesized proteins influence the structure and function of synapses. The ability to locally modulate protein synthesis in response to specific needs is a central feature of synaptic plasticity and hence, for learning and memory. Dysregulation of activity mediated protein synthesis has a significant impact on neuronal function and may lie at the root of many neurological disorders where the development and/or plasticity of the nervous system is impaired. The central focus of the lab is to understand the molecular mechanism of activity mediated protein synthesis in neurons. We are identifying the means and mechanism of activity-mediated protein synthesis and the implications for differentiation, plasticity and neurological disorders.
Our recent work has demonstrated the integral role of microRNAs and RNA-binding proteins in this process. We will investigate the functional involvement of microRNAs and RISC (RNA induced silencing complex) components in generating responses to neuronal activity. We will study the reversibility of microRNA inhibition and dynamics of RNA binding proteins as critical controls of activity mediated translation. The role of RNA binding proteins as molecular switches for the microRNA mediated machinery will be studied in conjunction with the dynamic storage function of RNA granules such as P bodies and stress granules.

Dysregulated synaptic protein synthesis is proposed to be the cause of fragile X syndrome (FXS), the most common inherited cause of cognitive deficiency. A major focus of the lab is to understand the function of FMRP (the protein that is absent in FXS patients) at synapses and elucidate the molecular mechanisms underlying FXS. We study the role of microRNAs in the etiology of FXS and the function of FMRP as a master control of synaptic protein synthesis. We are also interested in studying the involvement of FMRP in maintenance and differentiation of embryonic and adult neuronal stem cells. The mechanistic insight derived from our studies on FXS will be extended to other autism spectrum disorders. This collaborative work with Dr Sumantra Chattarji’s lab at NCBS is part of the new joint initiative on autism studies at NCBS, InStem and the University of Edinburgh.