A defining feature of neurodegenerative disorders is selective neuronal vulnerability—why some neurons degenerate while others are spared. Amyotrophic lateral sclerosis (ALS), an incurable neurodegenerative disorder, exemplifies disease-specific neuronal susceptibility as motor neurons responsible for muscle contraction undergo selective degeneration.
Now, a new study published in Nature Communications uncovers some of the biology behind this process. The paper, “Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model,” suggests that the cellular degradation load linked to cell size underlies motor neuron vulnerability and is a determinant of selective susceptibility in ALS. In addition, the work highlights a target of therapy and prevention in the alleviation of catabolic stress.
“Our findings suggest that the substantial size and metabolic demand of large motor neurons impose a constant degradation burden,” said Kazuhide Asakawa, PhD, associate professor, National Institute of Genetics in Japan. “This intrinsic pressure helps explain why these neurons are the first to degenerate in ALS, and points to reducing degradation burden as a potential therapeutic strategy.”
The team used single-cell–resolution imaging in zebrafish to show that large spinal motor neurons operate under a constant, intrinsic burden of protein and organelle degradation.
More specifically, by monitoring autophagy at single-cell resolution, they identified motor neurons as the cell population with the highest autophagic flux. These neurons maintain high baseline levels of autophagy, proteasome activity, and the unfolded protein response, suggesting a continuous struggle to maintain protein quality control. “Large spinal motor neurons (SMNs), most susceptible to ALS, exhibit higher flux compared to smaller SMNs and ALS-resistant ocular motor neurons,” the authors write.
This burden, they uncovered, is further amplified by the loss of TDP-43, a protein whose dysfunction is linked to most ALS cases. Initially, the acceleration of cellular degradation appears protective, supporting axon outgrowth. But over time, this heightened stress response may become overwhelmed, leading to the selective degeneration that characterizes ALS.
They note, “large SMNs accelerates both autophagy and proteasome-mediated degradation, which are further augmented by TDP-43 loss.”
The study not only provides direct evidence of cell size–linked proteostatic stress in vulnerable neurons, but also offers new insight into why ALS relentlessly targets motor neurons and remains so difficult to treat.