# Disease mechanism in ALS and frontotemporal dementia

> **NIH NIH R01** · LUDWIG INSTITUTE  FOR CANCER RES  LTD · 2020 · $647,454

## Abstract

Despite identification of more than twenty ALS-associated genes (at least half of which also cause the second
most frequent dementia, frontotemporal dementia or FTD), the disease mechanism(s) are unknown.
Exploiting transgenic and gene targeted mice we have constructed, as well as cell culture models, which we
have established with prior support from this grant application, we now propose a multi PI effort comprised of
three interrelated directions, each designed to uncover disease mechanism(s) underlying inherited and
sporadic ALS/FTD. First, in light of emerging genetic evidence for incomplete disease penetrance from single
mutations in C9orf72 and TDP-43 and identification of two or more ALS/FTD-linked gene mutations in multiple
sporadic ALS or FTD patients, we will test the hypothesis of oligogenic mutant gene synergy as a
cause/contributor of apparently sporadic ALS or FTD through use of multiple mouse lines each of which
develops only partial ALS- or FTD-like disease. Similarly, recognizing that heterozygous missense or
truncation mutants of Tank-binding kinase 1 (TBK1) have been identified as causative of ALS/FTD, we will
use our newly generated mouse models to determine how TBK1 contributes to motor neuron health and the
consequences of reduction of its activity, including determination of whether reduction in TBK1 synergizes with
other ALS-linked mutations to exacerbate motor neuron or cognitive disease in existing mouse lines that
develop only partial ALS- or FTD-like disease from TDP-43 or C9orf72 transgenes alone. Finally, the
discoveries of 1) liquid-liquid de-mixing as a mechanism for intracellular compartmentalization and 2) that such
repetitive phase separation can nucleate protein misfolding are seminal findings of extraordinary biological
interest and ones that have profound implications for neurodegenerative diseases. Recognizing this, we will
exploit three cell culture models that we have established in which de-mixing can be induced to identify
determinants, including the role of TBK1, of intracellular TDP-43 liquid-liquid de-mixing and aggregation, and to
determine if there is cell-to-cell transmission of aggregated TDP-43 and if so initiate tests of the mechanism(s)
of intercellular transmission.

## Key facts

- **NIH application ID:** 9977006
- **Project number:** 5R01NS027036-33
- **Recipient organization:** LUDWIG INSTITUTE  FOR CANCER RES  LTD
- **Principal Investigator:** Don W Cleveland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $647,454
- **Award type:** 5
- **Project period:** 1989-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977006

## Citation

> US National Institutes of Health, RePORTER application 9977006, Disease mechanism in ALS and frontotemporal dementia (5R01NS027036-33). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977006. Licensed CC0.

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