# Mechanism and function of MBNL mediated mRNA localization in neuronal development and neurologic disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $452,356

## Abstract

The development and maintenance of neurons and synaptic connections are highly complex processes, in part
due to the massive cytoplasmic volume and complex branching morphology of axons and dendrites. As one
mechanism, it is well appreciated that RNA localization and local translation are required to precisely regulate
protein homeostasis at synapses. Indeed, loss of FMRP in Fragile X Syndrome, or other impairments to RNA
localization and local translation at synapses, likely contribute to brain disorders. To better understand RNA
localization and local translation in neurons, we must elucidate the RNA cis-elements, RBP trans-factors, and
cytoskeletal motors mediating these processes. Although ongoing efforts have demonstrated how RNA binding
proteins (RBPs) can regulate local translation at post-synaptic sites, there still exists a major gap in our
understanding of how RBPs transport RNAs to regulate synaptic function. Fortunately, recent observations
provide clues about fruitful lines of investigation. For example, multiple studies report that distally localized
RNAs are enriched for cis-elements targeted by Muscleblind-like (MBNL) proteins. Although these
observations suggest that MBNL may be a major player in localizing RNAs to the pre- and post-synapse, we
still lack a mechanistic understanding for how MBNL proteins may achieve this task, or what functions depend
on MBNL-mediated RNA localization. This line of research has important implications for the neurological
disease myotonic dystrophy (dystrophia myotonica, DM), in which MBNLs are depleted by toxic CUG repeats.
Therefore, an emerging hypothesis is that RNA localization functions of MBNL are important for proper
synapse function, and that mis-localized RNAs might account for some neurological features of DM patients,
particularly early in disease. Here, using MBNL depletion and DM-associated models, we propose to identify
specific functions for the localization of MBNL targets. Aim 1 will elucidate mechanisms of MBNL-mediated
mRNA localization in neurons. We will define the RNA targets that are localized by MBNL in the pre- and post-synapse. We will characterize dynamic properties of motile MBNL RNA granules in live neurons and identify
cytoskeletal motors and adaptors associated with these granules. Using genomics, live cell imaging, and
biochemical approaches, we will establish mechanisms of how MBNL-interacting RNAs are transported. Aim 2
will define functions conferred by MBNL-dependent RNA localization using models of synapse development
and function, and models of myotonic dystrophy. By depleting cytoplasmic MBNL and other proteins required
for MBNL-dependent RNA localization, we will assess cellular functions dependent on this process. We will
identify specific neuronal functions, such as synaptic vesicle release, that depend on proper localization of
mRNAs by MBNL proteins. The impact of this research is to better understand how RNA localization and local
translation confers i...

## Key facts

- **NIH application ID:** 9866189
- **Project number:** 1R01NS114253-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** GARY J BASSELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $452,356
- **Award type:** 1
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866189

## Citation

> US National Institutes of Health, RePORTER application 9866189, Mechanism and function of MBNL mediated mRNA localization in neuronal development and neurologic disease (1R01NS114253-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9866189. Licensed CC0.

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