# Corticospinal neuron dysfunction and degeneration in ALS: testing the role of corticomotor connectivity in motor neuron disease

> **NIH NIH R01** · WINIFRED MASTERSON BURKE MED RES INST · 2021 · $726,701

## Abstract

Abstract (Summary): In patients with amyotrophic lateral sclerosis (ALS) and the related motor
neuron disease (MND) primary lateral sclerosis (PLS), deficits in motor control occur as a consequence
of the degeneration of corticospinal neurons (CSNs). ALS is more common than PLS, and genetically
more complex, with familial forms associated with causal mutations in over 30 ALS-related genes. In
these ALS mice, however, dysfunction and degeneration of CSNs have not been carefully examined,
and data implicating corticospinal (CS) circuits in these model systems of ALS is surprisingly limited.
One reason for this may be the very different pattern of connectivity between CSNs and spinal MNs in
humans vs. mice. In humans, CS axons located in the ventral and lateral funiculi form direct
connections with both MNs (cortico-motoneuronal (CM) connections) and interneurons. In contrast,
CS axons in mice are located mainly in the dorsal funiculus and only form indirect connections with
MNs through pre-motor interneurons. Therefore, we will use PlexinA1 mutant mice which have CM
connections together with ALS mouse models to analyze CS circuits. Our central hypothesis is that
progressive defects in CS circuitry in ALS mice will be exacerbated by the establishment of CM
connections. In Aim 1, we will determine formation of CS circuits in ALS mouse models with CM
connections. In Aim 2, we will determine function of CS circuits in ALS mouse models with CM
connections. In Aim 3, we will examine skilled movements in ALS mouse models with CM connections.
These studies will provide a model system to study mechanisms of CS degeneration in ALS/PLS, and
to test novel therapeutics targeting upper motor neuron dysfunction in these disorders.

## Key facts

- **NIH application ID:** 10099461
- **Project number:** 1R01NS119508-01
- **Recipient organization:** WINIFRED MASTERSON BURKE MED RES INST
- **Principal Investigator:** Neil Alan Shneider
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $726,701
- **Award type:** 1
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099461

## Citation

> US National Institutes of Health, RePORTER application 10099461, Corticospinal neuron dysfunction and degeneration in ALS: testing the role of corticomotor connectivity in motor neuron disease (1R01NS119508-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10099461. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*