| 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
|
| 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 |
