What is it about?
Native Americans used extracts from coniferous trees to treat paralysis, weakness and similar disorders. Drawing from this knowledge, we discovered that a small molecule from a conifer directly restores normal movement in a mouse model of the inherited human movement disorder, Episodic Ataxia Type 1. We also unlocked the molecular mechanism of therapy.
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Photo by Denise L on Unsplash
Why is it important?
The work is unique for three primary reasons. First, it uncovers a new mechanism for treating inherited dysfunction of ion channels, i.e., by a therapeutic small molecule co-opting the voltage sensor of a voltage-gated ion channel (in this case the potassium channel, Kv1.1), effectively converting the channel to a ligand-gated channel. This mechanism is dissected down to the atomic level using state-of-the-art all-atom Molecular Dynamics simulations. Second, the small molecule described is able to restore some or all function in ion channels with any of 12 different inherited sequence variants that cause human Episodic Ataxia Type 1. No other therapeutic has been shown to be this versatile for this or related disorders. Third, the work was inspired by Native American traditional medicine and is a rare if not unique example of this type of botanical therapeutic being now understood at the atomic level, while also being demonstrated to correct an inherited disease in an animal model, all in the same study. Because the small molecule (pisiferic acid) has been shown to be safe in subacute toxicity studies at much higher concentrations than its therapeutic range, it offers hope for future therapeutic development in Episodic Ataxia 1 and epilepsy, both of which are linked to mutations in the KCNA1 gene that encodes Kv1.1.
Perspectives
The research for this project involved field trips to remote and spectacular places to collect conifer samples, research into the rich history of Native American ethnobotany, deeply mechanistic experiments and computer simulations, culminating in successful testing in mice. I hope it helps readers to appreciate how essential it is to preserve our wild places, which are pharmaceutical treasure troves as well as inherently valuable for their beauty and natural grandeur. Equally important, I hope it helps to highlight the brilliance of indigenous traditional medicine and underline the importance of sustaining and championing indigenous cultures that still exist while also preserving their history and knowledge.
Professor Geoffrey W Abbott
University of California Irvine
Read the Original
This page is a summary of: A conifer metabolite corrects episodic ataxia type 1 by voltage sensor-mediated ligand activation of Kv1.1, Proceedings of the National Academy of Sciences, December 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2411816122.
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