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Author Notes:

djkatz@emory.edu

A.K.E. and D.J.K. designed research; A.K.E., A.C.W., R.A.M., S.M.K., Y.B., and D.J.K. performed research; A.K.E., A.C.W., R.A.M., D.A.M., S.M.K., Y.B., M.J.R., and D.J.K. analyzed data; and A.K.E. and D.J.K. wrote the paper.

We thank M. Rosenfeld (University of California San Diego) for providing Lsd1 deletion mice and D. Castrillon for providing the Vasa-Cre mice.

The authors declare no competing interest.

Subjects:

Research Funding:

We thank N. Seyfried, R. Betarbet, and Mr. Gearing, from the Emory University Alzheimer’s Disease Research Center (P50 AG025688), National Institute of Neurological Disorders and Stroke (NINDS), Emory University Neuroscience Core Facilities (P30NS055077) for tissue processing and providing PHF1 antibody; J. Alcudia of the Stanford University Gene Vector and Virus Core for help with virus generation and production; the Georgia Genomics and Bioinformatics Core, which provided the RNA library preparation and sequencing service; J. Schroeder from the Emory University Rodent Behavioral Core for help with rotatord and grid performance assays, supported by the Emory University Neuroscience NINDS Core Facilities (P30NS055077) with further support provided by the Georgia Clinical and Translational Science Alliance of the NIH under Award UL1TR002378; and J. Park from the Emory University Center for Systems Imagining for performing MRI supported by the National Center for Advancing Translational Sciences of the NIH under Award UL1TR000454. We would also like to thank M. J. Rowley and V. Corces for assistance in RNA sequencing analysis; K. Porter-Stransky and D. Weinshenker for providing PS19 Tau mice and for teaching the stereotaxic surgery procedure; L. R. Lym and Dr. Lerit for assistance with confocal imagining; and D. Weinshenker, A. Levey, C. Bean, and T. Caspary for comments on the manuscript and assistance throughout. Additionally we would like to thank fellow D.J.K. laboratory members for assistance experimentally and intellectually. A.K.E. was supported by the National Institute of General Medicine training grant (T32 GM008367-26) and a National Research Service Award Fellowship from NINDS (F31 NS098663-02). D.A.M. was supported by a research supplement to promote diversity in health-related research from NINDS (1R01NS087142). S.M.K. was supported by NINDS Training in Translational Research in Neurology grant (5T32 NS007480-17). M.J.R. is supported by the NIH Pathway to Independence Award K99/R00 GM127671. The work was supported by a grant to D.J.K. from NINDS (1R01NS087142).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • LSD1
  • neurodegeneration
  • tauopathy | Alzheimer's
  • Alzheimer's disease
  • epigenetics
  • PAIRED HELICAL FILAMENT
  • AMYLOID CASCADE HYPOTHESIS
  • ALZHEIMERS-DISEASE
  • NEUROFIBRILLARY TANGLES
  • MICROGLIAL ACTIVATION
  • BETA
  • PATHOLOGY
  • PHOSPHORYLATION
  • PROGRESSION
  • EXPRESSION

The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration

Journal Title:

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Volume:

Volume 117, Number 46

Publisher:

, Pages 29133-29143

Type of Work:

Article | Final Publisher PDF

Abstract:

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our laboratory implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer’s disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopathy mouse model to demonstrate that pathological tau can exclude LSD1 from the nucleus in neurons. In addition, we show that reducing LSD1 in these mice is sufficient to highly exacerbate tau-mediated neurodegeneration and tau-induced gene expression changes. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration and counteract tau-induced expression changes. These results suggest that inhibiting LSD1 via sequestration contributes to tau-mediated neurodegeneration. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimer’s disease.

Copyright information:

© 2020 The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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