PUBLICATION
A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models
- Authors
- Lin, C.Y., Lee, B.C., Zhang, P.H., Lu, S.C., Chang, W.Z., Wang, C.C., Tsai, H.J.
- ID
- ZDB-PUB-251127-12
- Date
- 2025
- Source
- Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics : e00806e00806 (Journal)
- Registered Authors
- Lee, Bing-Chang, Lin, Cheng-Yung, Tsai, Huai-Jen
- Keywords
- Amyotrophic lateral sclerosis, Motor neuron, Phosphoglycerate kinase 1, SOD1-G93A mice, Zebrafish
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/drug therapy
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/metabolism
- Amyotrophic Lateral Sclerosis*/pathology
- Animals
- Disease Models, Animal
- Disease Progression
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Motor Neurons*/drug effects
- Motor Neurons*/metabolism
- Motor Neurons*/pathology
- Nerve Degeneration*/drug therapy
- Nerve Degeneration*/pathology
- Neuroprotective Agents*/pharmacology
- Neuroprotective Agents*/therapeutic use
- Peptides*/pharmacology
- Peptides*/therapeutic use
- Phosphoglycerate Kinase
- Zebrafish
- PubMed
- 41298223 Full text @ Neurotherapeutics
Citation
Lin, C.Y., Lee, B.C., Zhang, P.H., Lu, S.C., Chang, W.Z., Wang, C.C., Tsai, H.J. (2025) A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. :e00806e00806.
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping