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

View ORCID ProfileIsrael Hernandez¹,*,
Gabriel Luna¹,*,
Jennifer N. Rauch¹,
View ORCID ProfileSurya A. Reis²,
View ORCID ProfileMichel Giroux¹,
View ORCID ProfileCeleste M. Karch ³,
Daniel Boctor¹,
View ORCID ProfileYoussef E. Sibih¹,
Nadia J. Storm ⁴,
Antonio Diaz⁴,
View ORCID ProfileSusmita Kaushik⁴,
Cezary Zekanowski⁵,
View ORCID ProfileAlexander A. Kang¹,
Cassidy R. Hinman¹,
View ORCID ProfileVesna Cerovac¹,
Elmer Guzman¹,
View ORCID ProfileHonjun Zhou¹,
View ORCID ProfileStephen J. Haggarty²,
Alison M. Goate⁶,
Steven K. Fisher ¹,⁷,
Ana M. Cuervo ⁴ and
View ORCID ProfileKenneth 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

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Gabriel Luna

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Jennifer N. Rauch

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Surya A. Reis

2Department 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

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Celeste M. Karch

3Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.

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Daniel Boctor

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Youssef E. Sibih

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Nadia J. Storm

4Department 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

4Department 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

4Department 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

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

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Alexander A. Kang

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Cassidy R. Hinman

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Vesna Cerovac

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Elmer Guzman

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Honjun Zhou

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Stephen J. Haggarty

2Department 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

6Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Steven K. Fisher

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

7Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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Ana M. Cuervo

4Department 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

1Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

7Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.

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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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