A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy

Israel Hernandez, Gabriel Luna, Jennifer N. Rauch, Surya A. Reis, Michel Giroux, Celeste M. Karch, Daniel Boctor, Youssef E. Sibih, Nadia J. Storm, Antonio Diaz, Susmita Kaushik, Cezary Zekanowski, Alexander A. Kang, Cassidy R. Hinman, Vesna Cerovac, Elmer Guzman, Honjun Zhou, Stephen J. Haggarty, Alison M. Goate, Steven K. Fisher & 2 others Ana Maria Cuervo, Kenneth S. Kosik

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalScience Translational Medicine
Volume11
Issue number485
DOIs
StatePublished - Jan 1 2019

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Tauopathies
Farnesyltranstransferase
Lysosomes
Pathology
Brain
Sumoylation
ras Proteins
Induced Pluripotent Stem Cells
tau Proteins
Frontotemporal Dementia
Mutation
Ubiquitination
Post Translational Protein Processing
Neurodegenerative Diseases
Small Interfering RNA
Atrophy
lonafarnib
Clinical Trials
Safety
Neurons

ASJC Scopus subject areas

  • Medicine(all)

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Hernandez, I., Luna, G., Rauch, J. N., Reis, S. A., Giroux, M., Karch, C. M., ... Kosik, K. S. (2019). A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Science Translational Medicine, 11(485). https://doi.org/10.1126/scitranslmed.aat3005

A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. / Hernandez, Israel; Luna, Gabriel; Rauch, Jennifer N.; Reis, Surya A.; Giroux, Michel; Karch, Celeste M.; Boctor, Daniel; Sibih, Youssef E.; Storm, Nadia J.; Diaz, Antonio; Kaushik, Susmita; Zekanowski, Cezary; Kang, Alexander A.; Hinman, Cassidy R.; Cerovac, Vesna; Guzman, Elmer; Zhou, Honjun; Haggarty, Stephen J.; Goate, Alison M.; Fisher, Steven K.; Cuervo, Ana Maria; Kosik, Kenneth S.

In: Science Translational Medicine, Vol. 11, No. 485, 01.01.2019.

Research output: Contribution to journalArticle

Hernandez, I, Luna, G, Rauch, JN, Reis, SA, Giroux, M, Karch, CM, Boctor, D, Sibih, YE, Storm, NJ, Diaz, A, Kaushik, S, Zekanowski, C, Kang, AA, Hinman, CR, Cerovac, V, Guzman, E, Zhou, H, Haggarty, SJ, Goate, AM, Fisher, SK, Cuervo, AM & Kosik, KS 2019, 'A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy' Science Translational Medicine, vol. 11, no. 485. https://doi.org/10.1126/scitranslmed.aat3005
Hernandez, Israel ; Luna, Gabriel ; Rauch, Jennifer N. ; Reis, Surya A. ; Giroux, Michel ; Karch, Celeste M. ; Boctor, Daniel ; Sibih, Youssef E. ; Storm, Nadia J. ; Diaz, Antonio ; Kaushik, Susmita ; Zekanowski, Cezary ; Kang, Alexander A. ; Hinman, Cassidy R. ; Cerovac, Vesna ; Guzman, Elmer ; Zhou, Honjun ; Haggarty, Stephen J. ; Goate, Alison M. ; Fisher, Steven K. ; Cuervo, Ana Maria ; Kosik, Kenneth S. / A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. In: Science Translational Medicine. 2019 ; Vol. 11, No. 485.
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AU - Sibih, Youssef E.

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AU - Zhou, Honjun

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