Novel insights into protein-mediated motor neuron loss in amyotrophic lateral sclerosis

In patients with ALS, the motor dysfunction symptoms usually appear in one part of the body, such as the limbs, and then progress to others. This further suggests that degeneration starts in one type of motor neuron and, thereafter, propagates to other motor-related neurons. Previous studies have highlighted the accumulation of TDP-43 in motor neurons as a co-occurrence with ALS.

The researchers developed ALS mouse models that primarily accumulate TDP-43 in the cortical motor neurons, spinal motor neurons, or skeletal muscles. They then examined how the TDP-43 in specific motor neurons initiates disease progression to other motor-related neurons.

The researchers found that TDP-43 induced in the cortical neurons of the mouse ALS models caused mild degeneration. They further found that TDP-43 was transported along the axons and transferred to the oligodendrocytes—non-neuronal cells that support neurons by enwrapping axons with a protective layer called myelin to facilitate neuronal signal transmission.

In contrast, TDP-43 induced in the spinal motor neurons did not spread to other cortical or spinal neurons but broadly induced cell death in the motor neurons and other neighboring neurons in the spinal cord. In addition, it led to severe atrophy of the muscles, which further led to motor dysfunction.

Their data revealed that TDP-43 spreads across neuroglial connections in the motor pathway and causes different pathological events to degenerate the spinal cord, suggesting that TDP-43 has distinct mechanisms for degeneration in the motor circuits of ALS.

Reference: TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models, Acta Neuropathologica, DOI 10.1007/s00401-023-02615-8