2025-10-28 国立遺伝学研究所
図:A) 大型の運動ニューロンでは、タンパク質を分解する活性(オートファジー流動)が高い。GFP-LC3はオートファジーにより分解される。矢印は、GFP-LC3の分解が活発な大型運動ニューロン。
B)オートファジーを阻害すると運動ニューロンの神経軸索の発達が阻害される(右)。スケールバーは20µm。
<関連情報>
- https://www.nig.ac.jp/nig/ja/2025/10/research-highlights_ja/pr20251028.html
- https://www.nig.ac.jp/nig/images/research_highlights/PR20251028.pdf
- https://www.nature.com/articles/s41467-025-65097-0
ゼブラフィッシュモデルのALS感受性運動ニューロンにおけるTDP-43の喪失により、本質的に加速された細胞分解が増幅される 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 & Koichi Kawakami
Nature Communications Published:27 October 2025
DOI:https://doi.org/10.1038/s41467-025-65097-0
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.
