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Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS.
Chang, Yu-Jen; Lin, Kai-Tai; Shih, Orion; Yang, Chi-Hua; Chuang, Ching-Yu; Fang, Ming-Han; Lai, Wei-Bin; Lee, Yi-Chung; Kuo, Hung-Chih; Hung, Shang-Cheng; Yao, Chi-Kuang; Jeng, U-Ser; Chen, Yun-Ru.
Afiliación
  • Chang YJ; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
  • Lin KT; Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Taiwan University and Academia Sinica, Taipei 115, Taiwan.
  • Shih O; National Synchrotron Radiation Research Center, Hsinchu 300, Taiwan.
  • Yang CH; Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
  • Chuang CY; National Synchrotron Radiation Research Center, Hsinchu 300, Taiwan.
  • Fang MH; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
  • Lai WB; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
  • Lee YC; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
  • Kuo HC; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
  • Hung SC; Department of Neurology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
  • Yao CK; Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
  • Jeng US; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan.
  • Chen YR; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
Sci Adv ; 10(8): eadj0347, 2024 Feb 23.
Article en En | MEDLINE | ID: mdl-38394210
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Amiotrófica Lateral Límite: Animals / Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Amiotrófica Lateral Límite: Animals / Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Estados Unidos