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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 (, 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 (, 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. "Rapamycin can have both positive and negative effects and this new molecule could give us a way to go after the toxic proteins without those complications," said Buck Professor Ellerby, director of the study, who added that the findings are also significant for the aging field. "We know that FKBP's get dysregulated during aging, a phenomenon which likely contributes to the accumulation of toxic proteins associated with other age-related diseases. SAFit2, which is neuroprotective, could give us another option to promote autophagy and clear out disease-causing proteins or proteins accumulated during disease and aging which are correlated with other conditions." FKPB51 has been implicated in Parkinson's and Alzheimer's diseases, as well as post-traumatic stress disorder and schizophrenia.

The first author of the work, Barbara Bailus, PhD, is a former postdoc in the Ellerby lab. "The fact that SAFit2 crosses the blood brain barrier is significant," said Dr. Bailus, who is now an Assistant Professor of Genetics at the Keck Graduate Institute in Claremont, California. "In our mouse models of HD, the small molecule interacted with FKPBP51 and cleared toxic proteins in both the cortex and the striatum which is part of the neural circuit necessary for voluntary movement."

The Ellerby lab will do pre-clinical work with SAFit2, which was developed by a collaborator, Dr. Felix Hausch, PhD, at the Technical University in Darmstadt, Germany.


In summary, the authors noted that “we found that FKBP5 levels are altered in HD and that lowering the levels of FKBP5 reduced mHTT in HD models both in vitro and in vivo, suggesting FKBP5 as a therapeutic target for HD. Notably, FKBP5 knockout murine models exhibit few phenotypic changes or behavioral alterations supporting the modulation of FKBP5 as a therapeutic target for neurological diseases. Our results suggest a model in which lowering the levels or activity of FKBP5 leads to increased autophagy, a structural change in the HTT protein likely due to a change in a proline site(s) in the protein, and subsequent clearance of the protein. Future studies will systematically evaluate if pharmacological or genetic modulation of this enzyme is beneficial in preclinical studies using HD mouse models.”


The recent failure of an experimental drug tested in Europe and Canada against HD highlights the desperation of patients who are forced to deal with a malady that usually sees it victims dying about 20 years following the onset of observable symptoms. The drug was developed by Ionis and Roche, and is an antisense oligonucleotide (ASO). It was designed to silence the gene responsible for HD, and had to be injected into the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. While the details of the failed trial are not published yet, Dr. Ellerby says the drug appeared not to diffuse into the entire brain, the ASOs may have had unanticipated toxic effects, and the ASOs do not reach all affected peripheral tissues. HD affects coordination and leads to cognitive decline and psychiatric problems.

"While we had hoped that this drug would ultimately work for patients in desperate need of treatment, those of us in the field have been aware that we need less invasive treatments for HD that are more likely to be easily tolerated," said Dr. Ellerby. "I don't know if we'll be able to do that with this small molecule, but at this point it does show potential and we look forward to evaluating its effects in pre-clinical experiments."

Other collaborators include Stephen Scheeler, Jesse Simons, Maria A. Sanchez, Swati Naphade, Alejandro Lopez-Ramirez, Ningzhe Zhang, Kuruwitage Lakshika Madushani, Stanislav Moroz, Ashley Loureiro, Kathrine H. Schreiber, and Brian Kennedy at the Buck Institute; Jordi Creus-Muncunill and Michelle E. Ehrlich, in the Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York; and Feliz Hausch, at the Institute for Organic Chemistry and Biochemistry, Technische Universitat Darmstadt, Darmstadt, Germany.


At the Buck Institute for Research on Aging (, researchers aim to end the threat of age-related diseases for this and future generations. The Institute brings together the most capable and passionate scientists from a broad range of disciplines to study mechanisms of aging and to identify therapeutics that slow down aging. The Institute’s goal is to increase human health span, or the healthy years of life. Located just north of San Francisco, the Buck Institute is globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer's, Parkinson's, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer. Its success will ultimately change healthcare.

[News Release] [Autophagy article] [Buck Institute for Aging Research]