Chang, Y.J., Lin, K.T., Shih, O., Yang, C.H., Chuang, C.Y., Fang, M.H., Lai, W.B., Lee, Y.C., Kuo, H.C., Hung, S.C., Yao, C.K., Jeng, U.S., Chen, Y.R. (2024). Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS.  Sci. Adv. 10(8): eadj0347.

FBrf0258817

Research paper

Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation among amyotrophic lateral sclerosis (ALS) patients. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs) where poly-glycine-arginine (GR) and poly-proline-arginine (PR) are most toxic. The structure-function relationship is still unknown. Here, we examined the minimal neurotoxic repeat number of poly-GR and found that extension of the repeat number led to a loose helical structure disrupting plasma and nuclear membrane. Poly-GR/PR bound to nucleotides and interfered with transcription. We screened and identified a sulfated disaccharide that bound to poly-GR/PR and rescued poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons. The compound rescued the shortened life span and defective locomotion in poly-GR/PR expressing Drosophila model and improved motor behavior in poly-GR-injected mouse model. Overall, our results reveal structural and toxicity mechanisms for poly-GR/PR and facilitate therapeutic development for C9-ALS.

PMC10889363 (PMC) (EuropePMC)