# Axonal dying back of upper motor neurons in human ALS

## TL;DR

This study finds that upper motor neuron axons degenerate in ALS patients, likely triggered by lower motor neuron degeneration and inflammation.

## Contribution

The study reveals a novel mechanism of upper motor neuron axonal degeneration in ALS, independent of disease onset location.

## Key findings

- Upper motor neuron degeneration occurs in the brainstem but not in cortical neurons.
- Inflammation and lower motor neuron degeneration may directly trigger upper motor neuron axonal loss.
- pTDP43 aggregates are present in lower motor neurons but not in upper motor neurons.

## Abstract

Patients with amyotrophic lateral sclerosis (ALS) present with arm, leg, or bulbar weakness with or without spasticity. While genetics plays a clear role in a subset of cases, it cannot explain why symptoms start focally or how upper (UMN) and lower motor neuron (LMN) systems are linked. Here, we examined the clinicopathological relationships between UMN and LMN disease in ten ALS patients. Detailed clinical assessments were obtained and tissues from the motor cortex, brainstem, and spinal cord were collected via a rapid autopsy protocol. Tissues were stained for UMN/LMN, myelin, axons, microglia, and pTDP43. Total RNA-sequencing was performed in the medulla, cervical, and lumbar spinal cords from each patient to identify pathways enriched at sites of disease onset. None of the patients had symptoms of frontotemporal dementia (FTD), but all had focal sites of clinical onset and spasticity, indicating both UMN and LMN involvement. Postmortem examination showed LMN degeneration and microglial activation were highest at sites of disease onset. In contrast, UMN degeneration of the corticospinal tract (CST) was present equally at all levels of the spinal cord up through the medulla, regardless of the site of disease onset. Surprisingly, there was no evidence of UMN degeneration of cortical motor neurons or their projecting axons above the brainstem. Similarly, while extensive pTDP43 aggregates were seen in degenerating LMNs, no pTDP43 aggregates were seen in UMN cell bodies or their axons. Mechanistically, RNA-sequencing implicated inflammatory pathways, especially at sites of disease onset. Our findings suggest that many ALS patients without FTD have a dying back of UMN axons, independent of the site of disease onset, which stops in the brainstem with preservation of cortical motor neurons and their proximal axons. Our findings suggest that UMN axonal degeneration can be directly triggered by LMN degeneration and inflammation.