Research Overview

Detailed transcriptomic analyses of human Alzheimer's disease and frontotemporal dementia brains have revealed that post-transcriptional regulation of RNA, including mRNA alternative splicing, stability, and trafficking, is deeply implicated in neurodegenerative disease. However, the precise mechanisms by which altered RNA processing and transport contribute to synaptic dysfunction and neurodegeneration remain unclear. Current approaches are not able to capture the complex, dynamic nature of mRNA processing and transport in neurons, particularly in the axons and dendrites. There is a need to integrate transcriptomics with spatial and temporal localization of mRNAs in vivo and in individual neurons.

In the Gopal Laboratory, we use live cell imaging, single-molecule FISH, super-resolution microscopy, and quantitative image analysis to study neuronal mRNA/ribonucleoprotein trafficking and the biophysics of mRNA-protein interactions in primary neurons and in human brain tissue. We also take advantage of recent advances in CRISPR/Cas9 genome editing technology and induced pluripotent stem cell (iPSC) biology to develop a powerful set of cellular and molecular tools that integrate live cell imaging/pulse-chase labeling techniques, biochemical, proteomic and transcriptomic analyses, and a high-throughput CRISPRi genetic screen to identify novel homeostatic mechanisms and molecular determinants of RNA-protein dynamics in human iPSC-derived neurons.