TY - JOUR
T1 - Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration
AU - Saito-Diaz, Kenyi
AU - Dietrich, Paula
AU - Saini, Tripti
AU - Rashid, Md Mamunur
AU - Wu, Hsueh Fu
AU - Ishan, Mohamed
AU - Sun, Xin
AU - Bedillion, Sydney
AU - Patel, Archie Jayesh
AU - Prudden, Anthony Robert
AU - Wzientek, Camryn Gale
AU - Knight, Trinity Nora
AU - Chen, Ya Wen
AU - Boons, Geert Jan
AU - Chen, Shuibing
AU - Studer, Lorenz
AU - Tiemeyer, Michael
AU - Xu, Bingqian
AU - Dragatsis, Ioannis
AU - Liu, Hong Xiang
AU - Zeltner, Nadja
N1 - Publisher Copyright:
Copyright © 2024 The Authors.
PY - 2024/11/20
Y1 - 2024/11/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85210340335&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adq2418
DO - 10.1126/scitranslmed.adq2418
M3 - Article
C2 - 39565876
AN - SCOPUS:85210340335
SN - 1946-6234
VL - 16
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 774
M1 - eadq2418
ER -