# The Convergence of Titin and Elongator in Amyotrophic Lateral Sclerosis

> **NIH NIH R15** · MONTANA STATE UNIVERSITY -BILLINGS · 2022 · $385,521

## Abstract

Project Summary
Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that ravages motor
neurons and the voluntary muscles they innervate, is the most common motor neuron disease.
Nucleolar stress was recently identified as an underlying pathogenic mechanism in ALS,
common to both familial and sporadic forms, that triggers the degeneration of motor neurons.
This proposal describes the discovery that titin, the largest protein in the human proteome, is
present in the nucleolus of motor neurons and seeks to demonstrate that its function in this
organelle and its regulation by the Elongator complex converge on the nucleolus as a nexus of
disease pathogenesis in ALS. The proposal includes three Aims. In the first aim, titin’s
presence in neurons will be fully characterized including identification of the specific central and
peripheral nervous system cell types that exhibit nucleolar. The second aim will test the
hypothesis that titin, encoded by TTN, is required for motor neuron homeostasis and that titin
dysfunction represents a novel underlying pathogenic mechanism in ALS. The use of a
conditional knockout mouse where TTN is selectively ablated in motor neurons will serve as a
powerful approach for investigating this hypothesis. The third aim seeks to understand why
mutations in the Elongator complex are associated with ALS and posits that Elongator may
actually regulate the production of titin as a common underlying mechanism of disease. Mice in
which the Elongator protein 1 (Elp1) is selectively ablated in motor neurons exhibit severely
compromised motor function, demonstrating that the loss of Elp1 is sufficient to arrive at an ALS
phenotype. These mice again provide a powerful tool for investigating Elongator targets whose
misregulation contribute to ALS. Accomplishment of the described specific aims will
significantly advance our understanding of the underlying molecular and cellular pathways that
go awry to precipitate the onset and progression of ALS and will identify new targets for the
development of effective therapeutics to treat the disease.

## Key facts

- **NIH application ID:** 10580407
- **Project number:** 2R15NS090384-03A1
- **Recipient organization:** MONTANA STATE UNIVERSITY -BILLINGS
- **Principal Investigator:** LYNN D GEORGE
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,521
- **Award type:** 2
- **Project period:** 2015-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580407

## Citation

> US National Institutes of Health, RePORTER application 10580407, The Convergence of Titin and Elongator in Amyotrophic Lateral Sclerosis (2R15NS090384-03A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10580407. Licensed CC0.

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