A Farnesyltransferase Inhibitor Activates Lysosomes and Reduces Tau Pathology in Mice With Tauopathy
Israel Hernandez1, Gabriel Luna1, Jennifer N Rauch1, Surya A Reis2, Michel Giroux1, Celeste M Karch3, Daniel Boctor1, Youssef E Sibih1, Nadia J Storm4, Antonio Diaz4, Susmita Kaushik4, Cezary Zekanowski5, Alexander A Kang1, Cassidy R Hinman1, Vesna Cerovac1, Elmer Guzman1, Honjun Zhou1, Stephen J Haggarty2, Alison M Goate6, Steven K Fisher1,7, Ana M Cuervo4, Kenneth S Kosik8,7
- Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
- Department of Neurology, Massachusetts General Hospital, Chemical Neurobiology Lab, and Center for Genomic Medicine, Harvard Medical School, Boston, MA 02114, USA.
- Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
- Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY 10461, USA.
- Laboratory of Neurogenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland.
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
- Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. kenneth.kosik@lifesci.ucsb.edu.
Abstract
Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell-derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.