Search for: All records

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. 

Abstract We present high-cadence photometric and spectroscopic observations of supernova (SN) 2024ggi, a Type II SN with flash spectroscopy features, which exploded in the nearby galaxy NGC 3621 at ∼7 Mpc. The light-curve evolution over the first 30 hr can be fit by two power-law indices with a break after 22 hr, rising fromM_V≈ −12.95 mag at +0.66 day toM_V≈ −17.91 mag after 7 days. In addition, the densely sampled color curve shows a strong blueward evolution over the first few days and then behaves as a normal SN II with a redward evolution as the ejecta cool. Such deviations could be due to interaction with circumstellar material (CSM). Early high- and low-resolution spectra clearly show high-ionization flash features from the first spectrum to +3.42 days after the explosion. From the high-resolution spectra, we calculate the CSM velocity to be 37 ± 4 km s⁻¹. We also see the line strength evolve rapidly from 1.22 to 1.49 days in the earliest high-resolution spectra. Comparison of the low-resolution spectra with CMFGEN models suggests that the pre-explosion mass-loss rate of SN 2024ggi falls in the range of 10⁻³–10⁻²M_☉yr⁻¹, which is similar to that derived for SN 2023ixf. However, the rapid temporal evolution of the narrow lines in the spectra of SN 2024ggi (R_CSM∼ 2.7 × 10¹⁴cm) could indicate a smaller spatial extent of the CSM than in SN 2023ixf (R_CSM∼ 5.4 × 10¹⁴cm), which in turn implies a lower total CSM mass for SN 2024ggi.