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; Ana M. Cuervo; Kenneth S. Kosik

doi:10.1126/scitranslmed.aat3005

Research ArticleNeurodegenerative Disease

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. Karch ³,
Daniel Boctor¹,
Youssef E. Sibih¹,
Nadia J. Storm ⁴,
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. Fisher ¹,⁷,
Ana M. Cuervo ⁴ and
Kenneth S. Kosik ¹,⁷,†

¹Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
²Department of Neurology, Massachusetts General Hospital, Chemical Neurobiology Lab, and Center for Genomic Medicine, Harvard Medical School, Boston, MA 02114, USA.
³Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
⁴Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY 10461, USA.
⁵Laboratory of Neurogenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland.
⁶Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

↵†Corresponding author. Email: kenneth.kosik{at}lifesci.ucsb.edu

↵* These authors contributed equally to this work.

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Science Translational Medicine 27 Mar 2019:
Vol. 11, Issue 485, eaat3005
DOI: 10.1126/scitranslmed.aat3005

Israel Hernandez

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Gabriel Luna

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Jennifer N. Rauch

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Surya A. Reis

Department of Neurology, Massachusetts General Hospital, Chemical Neurobiology Lab, and Center for Genomic Medicine, Harvard Medical School, Boston, MA 02114, USA.

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Michel Giroux

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Celeste M. Karch

Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.

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Daniel Boctor

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Youssef E. Sibih

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Nadia J. Storm

Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY 10461, USA.

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Antonio Diaz

Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY 10461, USA.

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Susmita Kaushik

Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY 10461, USA.

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Cezary Zekanowski

Laboratory of Neurogenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland.

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Alexander A. Kang

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Cassidy R. Hinman

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Vesna Cerovac

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Elmer Guzman

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Honjun Zhou

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Stephen J. Haggarty

Department of Neurology, Massachusetts General Hospital, Chemical Neurobiology Lab, and Center for Genomic Medicine, Harvard Medical School, Boston, MA 02114, USA.

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Alison M. Goate

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Steven K. Fisher

Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Ana M. Cuervo

Department of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY 10461, USA.

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Kenneth S. Kosik

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For correspondence: kenneth.kosik@lifesci.ucsb.edu

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

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