Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration.

Autor: Saito-Diaz K; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA., Dietrich P; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA., Saini T; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA., Rashid MM; Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA 30602, USA., Wu HF; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA., Ishan M; Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA 30602, USA., Sun X; College of Engineering, University of Georgia, Athens, GA 30602, USA., Bedillion S; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA., Patel AJ; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA., Prudden AR; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.; Department of Chemistry, University of Georgia, Athens, GA 30602, USA., Wzientek CG; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.; Department of Chemistry, University of Georgia, Athens, GA 30602, USA., Knight TN; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA., Chen YW; Department of Otolaryngology, Department of Cell, Developmental, and Regenerative Biology, Institute for Airway Sciences, Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Boons GJ; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.; Department of Chemistry, University of Georgia, Athens, GA 30602, USA.; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, 3508 TC Utrecht, Netherlands., Chen S; Department of Surgery and Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.; Center for Stem Cell Biology, Sloan Kettering Institute, New York, NY 10065, USA., Studer L; Center for Stem Cell Biology, Sloan Kettering Institute, New York, NY 10065, USA.; Department of Developmental Biology, Sloan Kettering Institute, New York, NY 10065, USA., Tiemeyer M; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.; Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA., Xu B; College of Engineering, University of Georgia, Athens, GA 30602, USA., Dragatsis I; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA., Liu HX; Regenerative Bioscience Center, Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA 30602, USA., Zeltner N; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.; Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Nov 20; Vol. 16 (774), pp. eadq2418. Date of Electronic Publication: 2024 Nov 20.
DOI: 10.1126/scitranslmed.adq2418
Abstrakt: The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the world's population suffers from nerve degeneration or peripheral nerve damage. Despite this, there are major gaps in the knowledge of human PNS development and degeneration; therefore, there are no available treatments. Familial dysautonomia (FD) is a devastating disorder caused by a homozygous point mutation in the gene ELP1 . FD specifically affects the development and causes degeneration of the PNS. We previously used patient-derived induced pluripotent stem cells (iPSCs) to show that peripheral sensory neurons (SNs) recapitulate the developmental and neurodegenerative defects observed in FD. Here, we conducted a chemical screen to identify compounds that rescue the SN differentiation inefficiency in FD. We identified that genipin restores neural crest and SN development in patient-derived iPSCs and in two mouse models of FD. Additionally, genipin prevented FD degeneration in SNs derived from patients with FD, suggesting that it could be used to ameliorate neurodegeneration. Moreover, genipin cross-linked the extracellular matrix (ECM), increased the stiffness of the ECM, reorganized the actin cytoskeleton, and promoted transcription of yes-associated protein-dependent genes. Last, genipin enhanced axon regeneration in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system) in in vitro axotomy models. Our results suggest that genipin has the potential to treat FD-related neurodevelopmental and neurodegenerative phenotypes and to enhance neuronal regeneration of healthy neurons after injury. Moreover, this suggests that the ECM can be targeted to treat FD.
Databáze: MEDLINE