# Structure of Triplet Repeat mRNA in Neurodegenerative Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $358,203

## Abstract

Triplet nucleotide repeat expansion mutations cause progressive and lethal neurodegenerative
diseases such as Huntington's Disease (HD) and Spinocerebellar ataxia type 2 (SCA2).
Although many mechanisms have been proposed to explain the pathological effects of triplet
repeat expansion mutations, the molecular basis for these diseases remains elusive. Most
research has focused on the toxic effects of expanded polyglutamine proteins encoded by CAG
repeats. However, triplet repeat RNA has recently been shown to be toxic to neurons and to
contribute to disease. This research will use a new X-ray footprinting technique to visualize the
abnormal structure of the expanded huntingtin mRNA in living neuronal cells. The first aim is to
determine the structures of normal and expanded RNA in unstressed and stressed cells that
mimic the neurotoxic effects of HD. Comparisons of different triplet repeat mRNAs will identify
sequences that readily form neurotoxic RNA structures. The second aim is to investigate how
interactions between triplet repeat RNA and cellular proteins contribute to neurotoxicity. In
addition, a tool compound that binds CAG RNA repeats will be tested for its ability to block
abnormal mRNA structures. The third aim is to determine whether the structures of triplet repeat
complexes and their effect on the mRNA interactome account for the varied sensitivity of
neurons to triplet repeat mutations. This first application of X-ray footprinting to mRNAs in cells
will link the three-dimensional structures of mRNAs with the pathology of triplet repeat diseases,
and determine how small molecule tool compounds disrupt these structures in live cells. The
long-term goal is to identify a structural signature of RNA-protein interactions that predict
neurotoxicity and that can be targeted by new therapies.

## Key facts

- **NIH application ID:** 9948009
- **Project number:** 5R01NS099397-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Wenzhen Duan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $358,203
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948009

## Citation

> US National Institutes of Health, RePORTER application 9948009, Structure of Triplet Repeat mRNA in Neurodegenerative Disease (5R01NS099397-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948009. Licensed CC0.

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