# Defining modifiers and mechanisms of RAN translation

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $771,846

## Abstract

Project Summary/Abstract
Defects in protein translation are central to multiple neurodegenerative diseases, including Alzheimer’s disease
and related dementias (e.g., frontotemporal lobar dementia). An unconventional form of translation has been
shown to play a role in several neurodegenerative diseases associated with nucleotide repeat diseases. In
these diseases, expanded nucleotide repeats get translated in an AUG-independent manner to produce
aberrant peptides that may contribute to neurodegeneration. The mechanism of this unusual form of
translation, called RAN translation, has remained poorly understood. The Gitler and Puglisi laboratories have
joined forces to combine biophysics and genetics approaches to elucidate the mechanism of RAN translation.
We developed new single-molecule methodologies to study translation dynamics in humans and combined
these with biochemical and in vivo approaches to reveal a global mechanism for RAN translation and identified
potent modifiers of RAN translation, at least one of which could mitigate degeneration in several frontotemporal
dementia and amyotrophic lateral sclerosis (ALS) disease models. We propose new studies to gain even
deeper understanding of RAN translation. We will also expand and extend our efforts to investigate a new facet
of frontotemporal dementia (FTD) pathology that we recently discovered – altered processing of the 3’ end of
certain mRNAs, which are targets of the FTD and ALS disease protein TDP-43. These altered 3’ ends of the
mRNAs has profound effects on the translation of the mRNAs and we have evidence that at least one of them
is directly linked to FTD. Our results will build on the foundation of the prior funding period and establish a
coherent dynamic mechanism of RAN translation and its regulation from initiation through protein production.
We will also illuminate a new facet of TDP-43 pathology in FTD and ALS and how this impacts protein
translation. More broadly, our results will provide a mechanistic foundation for understanding the interplay of
translation dynamics and fidelity and protein quality control in aging and neurodegenerative diseases, including
dementia.

## Key facts

- **NIH application ID:** 10882510
- **Project number:** 2R01AG064690-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Aaron D. Gitler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $771,846
- **Award type:** 2
- **Project period:** 2019-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882510

## Citation

> US National Institutes of Health, RePORTER application 10882510, Defining modifiers and mechanisms of RAN translation (2R01AG064690-02). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10882510. Licensed CC0.

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