Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model

Kazuhide Asakawa (), Takuya Tomita, Shinobu Shioya, Hiroshi Handa, Yasushi Saeki and Koichi Kawakami
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Kazuhide Asakawa: Mishima
Takuya Tomita: The University of Tokyo
Shinobu Shioya: Mishima
Hiroshi Handa: Tokyo Medical University
Yasushi Saeki: The University of Tokyo
Koichi Kawakami: Mishima

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Selective neuronal vulnerability is a defining feature of neurodegenerative disorders, exemplified by motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The nature of motor neurons underlying this selectivity remains unresolved. Here, by monitoring autophagy at single-cell resolution across the translucent zebrafish spinal cord, we identify motor neurons as the cell population with the highest autophagic flux. Large spinal motor neurons (SMNs), most susceptible to ALS, exhibit higher flux compared to smaller SMNs and ALS-resistant ocular motor neurons. Notably, large SMNs accelerates both autophagy and proteasome-mediated degradation, which are further augmented by TDP-43 loss. Additionally, acceleration of multiple unfolded protein response pathways indicates their innate tendency to accumulate misfolded proteins. Enhanced cellular degradation in large SMNs is neuroprotective as its inhibition halts axon outgrowth. These findings propose that cell size-associated degradation load underlies selective neuronal vulnerability in ALS, highlighting the alleviation of catabolic stress as a target of therapy and prevention.

Date: 2025
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DOI: 10.1038/s41467-025-65097-0

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