Pathologically mislocalised TDP-43 in upper motor neurons causes a die-forward spread of ALS-like pathogenic changes throughout the mouse corticomotor system

• Published in: Progress in neurobiology 2023-07, Vol.226, p.102449-102449, Article 102449
• Main Authors: Reale, Laura A., Dyer, Marcus S., Perry, Sharn E., Young, Kaylene M., Dickson, Tracey C., Woodhouse, Adele, Blizzard, Catherine A.
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; Cortical hyperexcitability; Corticomotor system; DNA-Binding Proteins - metabolism; Mice; Motor Neurons - metabolism; Motor Neurons - pathology; Pre-synaptic protein; Spinal Cord - metabolism; Spinal cord circuitry; TDP-43
• ISSN: 0301-0082; 1873-5118
• DOI: 10.1016/j.pneurobio.2023.102449

Alterations in upper motor neuron excitability are one of the earliest phenomena clinically detected in ALS, and in 97 % of cases, the RNA/DNA binding protein, TDP-43, is mislocalised in upper and lower motor neurons. While these are two major pathological hallmarks in disease, our understanding of where disease pathology begins, and how it spreads through the corticomotor system, is incomplete. This project used a model where mislocalised TDP-43 was expressed in the motor cortex, to determine if localised cortical pathology could result in widespread corticomotor system degeneration. Mislocalised TDP-43 caused layer V excitatory neurons in the motor cortex to become hyperexcitable after 20 days of expression. Following cortical hyperexcitability, a spread of pathogenic changes through the corticomotor system was observed. By 30 days expression, there was a significant decrease in lower motor neuron number in the lumbar spinal cord. However, cell loss occurred selectively, with a significant loss in lumbar regions 1–3, and not lumbar regions 4–6. This regional vulnerability was associated with alterations in pre-synaptic excitatory and inhibitory proteins. Excitatory inputs (VGluT2) were increased in all lumbar regions, while inhibitory inputs (GAD65/67) were increased in lumbar regions 4–6 only. This data indicates that mislocalised TDP-43 in upper motor neurons can cause lower motor neuron degeneration. Furthermore, cortical pathology increased excitatory inputs to the spinal cord, to which local circuitry compensated with an upregulation of inhibition. These findings reveal how TDP-43 mediated pathology may spread through corticofugal tracts in ALS and identify a potential pathway for therapeutic intervention. [Display omitted] •Two hypotheses exist for ALS pathogenesis origin: dying-forward (cortex→spinal cord) and dying-backward (spinal cord→cortex).•By experimentally expressing cytoplasmically targeted TDP-43 in the cortex, the dying-forward hypothesis was investigated.•Cortical TDP-43 pathology caused a spread of pathogenic changes through corticofugal tracts.•Lower motor neurons were differentially vulnerable to cortical pathology dependent on lumbar region.•Lower motor neurons were protected in regions where inhibitory pre-synaptic proteins were increased.