# RNA Processing-Mediated Mechanisms of CNS Dysfunction in Myotonic Dystrophy

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $557,280

## Abstract

Myotonic dystrophy (dystrophia myotonica, DM) is an autosomal dominant genetic disease, with a diagnosed
prevalence of 1:8000 people worldwide, that affects multiple tissues of the body, including skeletal muscle,
heart, and related to this proposal, the central nervous system (CNS). DM1 is caused by expanded CTG
repeats in the 3' UTR of dystrophia myotonica protein kinase (DMPK). There is substantial evidence in mouse
DM1 models and human DM1 postmortem tissue to support an RNA-mediated disease mechanism where
toxic intranuclear CUG RNA foci sequester Muscleblind (MBNL) RNA binding proteins that normally play
crucial roles to regulate various aspects of post-transcriptional gene regulation. A major gap in our
understanding is that we do not know which RNA processing defects underlie specific impairments in DM1
brain function. Recent work together with our new findings suggests that missplicing of RNAs encoding
synaptic proteins is responsible for CNS dysfunction in DM1. Our central hypothesis is that CNS phenotypes
are directly attributed to loss of MBNL mediated RNA processing and that restoration of MBNL activity and/or
splicing can restore brain function. Our goal is to gain a thorough understanding of RNA processing-mediated
mechanisms of CNS dysfunction in DM1 and use this to develop and rigorously evaluate novel therapeutic
strategies. The overall objectives of this proposal are to use both candidate and genome wide approaches,
applied to MBNL KO mice and a new AAV9 based neuronal mouse model, compared to RNAseq analysis of
human postmortem brain, to evaluate the role of specific splicing events to drive symptoms, and to
comprehensively identify changes in missplicing and RNA processing. Aim 1 will characterize how
dysregulation of GABRG2, GRIN1, and SNAP25 splicing events is linked to molecular, cellular, and behavioral
phenotypes observed in DM1. Aim 2 will develop a new AAV9 based mouse model to elucidate the set of RNA
processing events in neurons that cause DM1 phenotypes, through transcriptional profiling and overlap of
human DM brains with DM mouse model brains. Aim 3 will assess the extent to which antisense
oligonucleotides or MBNL expression can rescue molecular, cellular, physiologic and behavioral phenotypes in
DM1 mouse models. These studies will provide new mechanistic insights into how perturbations to specific
RNA processing events can lead to CNS symptoms in myotonic dystrophy, and provide a broader
comprehensive view of all transcriptome changes occurring in the DM CNS. The proposed work is significant,
as no molecular changes have been linked to any phenotypes in the DM CNS. This provides the framework for
future therapeutic efforts aimed at correcting CNS defects.

## Key facts

- **NIH application ID:** 10447080
- **Project number:** 5R01NS112291-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** GARY J BASSELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $557,280
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447080

## Citation

> US National Institutes of Health, RePORTER application 10447080, RNA Processing-Mediated Mechanisms of CNS Dysfunction in Myotonic Dystrophy (5R01NS112291-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447080. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*