Genipin Crosslinks the Extracellular Matrix to Rescue Developmental and Degenerative Defects, and Accelerates Regeneration of Peripheral Neurons.

Autor:	Saito-Diaz K; Center for Molecular Medicine, University of Georgia, Athens GA, USA., Dietrich P; Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN, USA., Wu HF; Center for Molecular Medicine, University of Georgia, Athens GA, USA.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens GA, USA., Sun X; College of Engineering, University of Georgia, Athens GA, USA., Patel AJ; Center for Molecular Medicine, University of Georgia, Athens GA, USA., Wzientek CG; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA., Prudden AR; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA., Boons GJ; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.; Department of Chemistry, University of Georgia, Athens, GA, USA.; Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, and Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands., Chen S; Department of Surgery and Department of Biochemistry at Weill Cornell Medical College, New York, NY, USA.; Center for Stem Cell Biology, Sloan Kettering Institute, New York, NY, USA., Studer L; Center for Stem Cell Biology, Sloan Kettering Institute, New York, NY, USA.; Department of Developmental Biology, Sloan Kettering Institute, New York, NY, USA., Xu B; College of Engineering, University of Georgia, Athens GA, USA., Dragatsis I; Department of Physiology, The University of Tennessee, Health Science Center, Memphis, TN, USA., Zeltner N; Center for Molecular Medicine, University of Georgia, Athens GA, USA.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens GA, USA.; Department of Cellular Biology, University of Georgia, Athens GA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 24. Date of Electronic Publication: 2023 Mar 24.
DOI:	10.1101/2023.03.22.533831
Abstrakt:	The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the population suffer nerve degeneration or peripheral damage. For example, over 40% of patients with diabetes or undergoing chemotherapy develop peripheral neuropathies. Despite this, there are major gaps in the knowledge of human PNS development and therefore, there are no available treatments. Familial Dysautonomia (FD) is a devastating disorder that specifically affects the PNS making it an ideal model to study PNS dysfunction. FD is caused by a homozygous point mutation in ELP1 leading to developmental and degenerative defects in the sensory and autonomic lineages. We previously employed human pluripotent stem cells (hPSCs) to show that peripheral sensory neurons (SNs) are not generated efficiently and degenerate over time in FD. Here, we conducted a chemical screen to identify compounds able to rescue this SN differentiation inefficiency. We identified that genipin, a compound prescribed in Traditional Chinese Medicine for neurodegenerative disorders, restores neural crest and SN development in FD, both in the hPSC model and in a FD mouse model. Additionally, genipin prevented FD neuronal degeneration, suggesting that it could be offered to patients suffering from PNS neurodegenerative disorders. We found that genipin crosslinks the extracellular matrix, increases the stiffness of the ECM, reorganizes the actin cytoskeleton, and promotes transcription of YAP-dependent genes. Finally, we show that genipin enhances axon regeneration in an in vitro axotomy model in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system, CNS). Our results suggest genipin can be used as a promising drug candidate for treatment of neurodevelopmental and neurodegenerative diseases, and as a enhancer of neuronal regeneration. Competing Interests: Competing interests: L.S. is a scientific co-founder and consultant and has received research support from BlueRock Therapeutics.
Databáze:	MEDLINE
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