# MiR-218 regulatory networks in adult mice and its relationship to ALS

> **NIH NIH R21** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2021 · $529,100

## Abstract

PROJECT SUMMARY/ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a relatively-rare disease that leads to motor neuron degeneration in
1:50,000 people in the US. Since mutations in ~50 different genes have been linked to ALS, there is the daunting
possibility that treatments will require the development of many separate therapies. Consequently, identification
of the shared pathways and key nodal points affected in multiple forms of sporadic and familial ALS could provide
greater impact for the overall ALS community. In this regard much effort is currently focused on pathways
relevant to protein-stasis, autophagy and cell stress, since protein aggregates are a common feature of ALS.
This proposal takes a complimentary approach by examining the mechanistic role played by an essential motor
neuron-specific microRNA (miR-218) that is affected by ALS.
Gene expression studies to identify microRNAs dysregulated in sporadic and familial ALS consistently detect
downregulation of miR-218. A recent analysis of ALS patients found a cohort with mutations in miR-218,
suggesting insufficient miR-218 levels/activity may be a risk factor for the disease. Because many ALS-linked
genes affect RNA metabolism and microRNA processing complexes, it is hypothesized that miR-218 activity is
downregulated in many types of ALS leading to a pattern of gene dysregulation that fails to sustain motor
neurons. Conversely, it is predicted that ectopic miR-218 may restore proper gene expression in motor neurons
and counteract ALS. While previous studies have established that miR-218 controls motor neuron connectivity
in embryos, the goal of this grant is to identify the gene networks controlled by miR-218 in adult motor neurons
using genetics to decrease (aim 1) and elevate (aim 2) miR-218 with precise spatiotemporal control. A floxed-
miR-218 allele was created and following Cre-mediated deletion in adult motor neurons it was found that
neuromuscular defects arose - indicating miR-218 is a critical regulatory molecule in mature motor neurons. In
Aim 1 miR-218 will be conditionally deleted in adult mouse motor neurons and next generation RNA sequencing
from single-nuclei will be used to (1a) uncover the miR-218 gene network in adult motor neurons, and (1b) cross-
correlate miR-218-regulated genes with dysregulated genes in mouse models of ALS. In Aim 2, miR-218 will
be conditionally (ectopically) expressed in mice to (2a) define non-cell-autonomous effects of mir-218, and (2b)
model baseline levels of miR-218 in motor neurons that would be tolerable for potential ALS-therapies.
These studies will pave the way for future experiments to directly test whether miR-218 can be used to attenuate
ALS. To make this possible an independent but complementary R03 was submitted (see complimentary
application) to allow others with ALS-models to explore this promising possibility with our miR-218 reagents. This
R21 grant is an important step toward understanding the mechanism-of-action of miR-218...

## Key facts

- **NIH application ID:** 10196817
- **Project number:** 1R21NS121846-01
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** SAMUEL L. PFAFF
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $529,100
- **Award type:** 1
- **Project period:** 2021-05-15 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196817

## Citation

> US National Institutes of Health, RePORTER application 10196817, MiR-218 regulatory networks in adult mice and its relationship to ALS (1R21NS121846-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10196817. Licensed CC0.

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