Novel Drug Candidate for Axon Regeneration
Philipp Gobrecht, Jeannette Gebel, Alexander Hilla, Günter Gisselmann, and Dietmar Fischer
(see article e2031232024)
Axon regeneration is required for nerve growth following injury, but there is a need for effective treatments promoting axon regrowth. A mechanism that opposes this process is tubulin detyrosination, which essentially reduces microtubule dynamics and compromises nerve regrowth. Recently, a drug candidate for motor and sensory nerve recovery called parthenolide was identified. It promotes adult sensory axon growth in culture by reducing detyrosination. In this issue, Gobrecht et al. used a dual genetic and pharmacological approach to uncover more about the mechanism through which parthenolide works. They first found that overexpressing vasohibins promoted detyrosination and increased the amount of parthenolide needed to facilitate axon growth. Genetic knockdown of vasohibins conversely promoted axon growth and exposure to either parthenolide or its orally bioavailable prodrug significantly improved sensory, motor, and sympathetic nerve regeneration in mice and rats. These findings support the use of parthenolide as a treatment for facilitating axon regrowth following nerve injury by targeting vasohibins.
L4 dorsal root ganglia stained for green fluorescent protein (GFP, green) and βIII-tubulin, which expresses in grown axons (tub, red). GFP transduced over 90% of sensory neurons on average. Scale bar, 200 µm.
A New Mouse Model for a Rare Disorder
Mark A. Deehan, Josine M. Kothuis, Ellen Sapp, Kathryn Chase, Yuting Ke et al.
(see article e1610232024)
Gene sequencing studies have revealed mutations underlying many neurodevelopmental disorders, including extremely rare ones. A mutation in the nucleus accumbens-associated 1 (NACC1) gene was found in seven children with severely detrimental symptoms including developmental delay, epilepsy, bilateral cataracts, delayed brain myelination, involuntary movements, no speech, and gastrointestinal distress. Since this discovery, other patients have been identified. While rare, the extreme discomfort and death that this disease can cause points to a need for the identification of treatment targets. To advance our understanding of how the NACC1 mutation causes this disease, Deehan et al. developed a new mouse model with this mutation that recapitulates patient symptoms. This model is important because it can be used to investigate the molecular underpinnings of the disease and to eventually test treatment options.
Footnotes
This Week in The Journal was written by Paige McKeon
