Overview
- A Nature Communications paper from Kazuhide Asakawa’s group reports that large spinal motor neurons maintain persistently elevated autophagy, proteasome activity, and unfolded protein response.
- Using single-cell–resolution measurements, the team found higher degradation activity in large spinal neurons than in smaller spinal neurons and in ALS-resistant ocular motor neurons.
- Genetic inactivation of TDP-43 further accelerated autophagy and proteasome-mediated degradation, intensifying cellular stress in the large, ALS-vulnerable population.
- The accelerated degradation initially supported axon outgrowth but became unsustainable over time, aligning with selective motor neuron degeneration observed in ALS.
- The authors suggest reducing the intrinsic degradation burden as a therapeutic strategy, while noting the results are preclinical in zebrafish and need validation in mammalian models.