Decipher how mRNAs are captured at specific subcellular locations to support local translation in neurons

Introduction

Brain function requires precise regulation of the neuronal proteome, which involves localizing thousands of mRNAs to neurites, where specific subsets are translated at the required subcellular locations. Although local translation is well-established, the mechanisms that ensure the capture and translation of specific mRNAs at the correct subcellular location remain elusive. A better understanding of this process is urgent since dysregulation of mRNA localization and translation is emerging as a key pathological event in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).

Project Aim

In RNA.ORG, I aim to define, at a molecular level, how the coordination between mRNA transport, capture, and local translation occurs to support neuronal function.

Background

Recent work from my lab and others has shown that multiple organelles interact with mRNA and translational machinery. This raises the exciting possibility that organelle interactions coordinate mRNA distribution, local capture, and selective translation. I have developed tools to visualize and manipulate organelle position and contacts at nanoscale resolution. Here, I will leverage these tools and directly control mRNA positioning to elucidate the importance of mRNA capture in neuronal function and intervene in its dysregulation in ALS.

Key Objectives

In combination with live-cell and super-resolution imaging, RNA-sequencing, and proteomics, this project will address the following key objectives:

1. Resolve the subcellular distribution and dynamics of neuronal organelle-mRNA contacts.
2. Unravel the functions of organelle-mediated mRNA capture at specific subcellular locations.
3. Determine the role of dysregulated mRNA capture in amyotrophic lateral sclerosis.

Expected Outcomes

RNA.ORG will elucidate novel mechanisms on the subcellular capture and translation of specific mRNAs in neurons and will provide new insights into the role of local mRNA positioning in neuronal development, physiology, and pathology.