Reference - Detail
| RRC ID | 87396 |
|---|---|
| Author | Asakawa K, Tomita T, Shioya S, Handa H, Saeki Y, Kawakami K. |
| Title | Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model. |
| Journal | Nat Commun |
| 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. |
| Volume | 16(1) |
| Pages | 9213 |
| Published | 2025-10-27 |
| DOI | 10.1038/s41467-025-65097-0 |
| PII | 10.1038/s41467-025-65097-0 |
| PMID | 41145518 |
| PMC | PMC12559720 |
| MeSH | Amyotrophic Lateral Sclerosis* / genetics Amyotrophic Lateral Sclerosis* / metabolism Amyotrophic Lateral Sclerosis* / pathology Animals Autophagy DNA-Binding Proteins* / genetics DNA-Binding Proteins* / metabolism Disease Models, Animal Humans Motor Neurons* / metabolism Motor Neurons* / pathology Proteasome Endopeptidase Complex / metabolism Proteolysis Spinal Cord / metabolism Spinal Cord / pathology Unfolded Protein Response Zebrafish Zebrafish Proteins* / genetics Zebrafish Proteins* / metabolism |
| IF | 12.121 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 57 |
| Altmetric score changes over past 6months | 0.5 |
| Resource | |
| Zebrafish | UAS:GFP-LC3-RFP-LC3∆G, SAGFF(LF)73A, SAIGFF213A, mnr2b-hs:Gal4, TDP-43DKO, UAS:hmCP2AGd410mT436A, UAS:mCherry-P2A-EGFP-d410m-T436A |