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Archive - Jun 2021

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June 2nd

Modulating Rapamycin Target Protein FKBP51 with Small Molecule SAFit2 Promotes Autophagy, Lowering Toxic Huntingtin Protein

Researchers world-wide are focused on clearing the toxic mutant Huntingtin protein that leads to neuronal cell death and systemic dysfunction in Huntington's disease (HD), a devastating, incurable, progressive neurodegenerative genetic disorder. Scientists in the lab of Buck Institute Professor Linda Ellerby (https://www.buckinstitute.org/lab/ellerby-lab/), PhD, lab have found that the targeting the protein called FK506-binding protein 51 (FKBP51) promotes the clearing of those toxic proteins via autophagy, a natural process whereby cells recycle damaged proteins and mitochondria and use them for nutrition. In an article published online on May 24, 2021 in Autophagy (https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1904489), researchers showed that FKBP51 promotes autophagy through a new mechanism that could avoid worrisome side effects associated with rapamycin, an immune-suppressing drug which also extends lifespan in mice. They show that both rapamycin and the small pharmacological inhibitor of FKBP51, SAFit2, protect HD neurons but that the mechanisms of the two drugs are distinct. The open-access Autophagy article is titled “Modulating FKBP5/FKBP51 and Autophagy Lowers HTT (Huntingtin) Levels.” Researchers focused on a family of binding proteins called FKBP's and specifically on FKBP51, which was most changed in mouse and human stem cell models of HD. During the course of the study, scientists found that FKBP51 acts on a pathway independent of mTOR (mammalian target of rapamycin), which is associated with rapamycin. Scientists also identified a small molecule, SAFit2, which crossed the blood-brain barrier and promoted autophagy and reduced the toxic disease-causing protein HTT through that mTOR-independent pathway.