Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration Journal Article
| Authors: | Saito-Diaz, K.; Dietrich, P.; Saini, T.; Rashid, M. M.; Wu, H. F.; Ishan, M.; Sun, X.; Bedillion, S.; Patel, A. J.; Prudden, A. R.; Wzientek, C. G.; Knight, T. N.; Chen, Y. W.; Boons, G. J.; Chen, S.; Studer, L.; Tiemeyer, M.; Xu, B.; Dragatsis, I.; Liu, H. X.; Zeltner, N. |
| Article Title: | Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration |
| Abstract: | 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. Copyright © 2024 The Authors. |
| Keywords: | controlled study; protein expression; survival analysis; human cell; mutation; nonhuman; flow cytometry; mouse; animal; metabolism; animals; mice; embryonic stem cell; animal experiment; animal model; cell differentiation; cytotoxicity; high throughput screening; immunofluorescence; drug effect; pathology; extracellular matrix; disease model; dimethyl sulfoxide; brain derived neurotrophic factor; sensory receptor cells; immunoblotting; cell migration; down regulation; upregulation; neural crest; disease models, animal; parkinson disease; cell interaction; cell adhesion; fluphenazine; nerve regeneration; axons; alzheimer disease; degenerative disease; cysteine rich protein 61; dysautonomia; peripheral nervous system; sensory nerve cell; induced pluripotent stem cells; ceftriaxone; fibronectin; nerve degeneration; transcription factor runx1; brain derived neurotrophic factor receptor; glial cell line derived neurotrophic factor; huntington chorea; atomic force microscopy; peripheral nerve injury; gene ontology; liquid chromatography-mass spectrometry; protein tyrosine kinase a; calcitonin gene related peptide; neurotrophin 3 receptor; nerve fiber regeneration; dopamine receptor blocking agent; neurotrophin receptor p75; nerve growth factor; dysautonomia, familial; uncoupling protein 2; peripherin; transcription factor pou4f1; transcription factor sox10; induced pluripotent stem cell; humans; human; article; rna sequencing; 4',6 diamidino 2 phenylindole; mrna expression level; real time reverse transcription polymerase chain reaction; crispr associated endonuclease cas9; collagen type i alpha 1 chain; iridoids; fibrillin 2; genipin; iridoid |
| Journal Title: | Science Translational Medicine |
| Volume: | 16 |
| Issue: | 774 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2024-11-20 |
| Start Page: | eadq2418 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.adq2418 |
| PUBMED: | 39565876 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
