# Cryo-EM Analysis of Ribosomal Defects in C9ORF72-Associated Frontotemporal Dementia and ALS

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $209,375

## Abstract

Abstract
Frontotemporal dementia (FTD), caused by atrophy of frontal and/or anterior temporal lobes, is
the second most common form of dementia after Alzheimer’s disease. FTD patients often show
changes in personality, loss of empathy and disinhibition, or language impairment and movement
deficits. The most common genetic cause of FTD is a GGGGCC (G4C2) repeat expansion in the
first intron of the C9ORF72 gene. The sense and antisense repeat RNAs are translated into 5
different dipeptide repeat (DPR) proteins that are observed in C9ORF72 patient brain neurons.
Among them, poly(GR) and poly(PR) are most toxic but it remains largely unknown which specific
molecular and structural mechanisms of action underly their neurotoxicity. In this R21 project, we
will examine the high-resolution structural mechanisms of poly(GR) and poly(PR) production by
the ribosome, the underlying cis-inhibition of translation by expanded G4C2 repeats and DPR
proteins, and translation dysregulation directly in FTD patient neurons. By discovering the
molecular mechanisms of C9ORF72-caused FTD and further developing tools for high-resolution
structural biology in neurons, our project may open new directions in neuroscience research and
therapeutics development of other molecular pathologies underlying dementia.

## Key facts

- **NIH application ID:** 10907041
- **Project number:** 5R21AG084170-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Fen-Biao Gao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2023-08-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907041

## Citation

> US National Institutes of Health, RePORTER application 10907041, Cryo-EM Analysis of Ribosomal Defects in C9ORF72-Associated Frontotemporal Dementia and ALS (5R21AG084170-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10907041. Licensed CC0.

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