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LSD1 protects against hippocampal and cortical neurodegeneration

Author

Listed:
  • Michael A. Christopher

    (Emory University School of Medicine
    Emory University)

  • Dexter A. Myrick

    (Emory University School of Medicine
    Emory University)

  • Benjamin G. Barwick

    (Emory University
    Emory University School of Medicine)

  • Amanda K. Engstrom

    (Emory University School of Medicine
    Emory University)

  • Kirsten A. Porter-Stransky

    (Emory University School of Medicine)

  • Jeremy M. Boss

    (Emory University School of Medicine)

  • David Weinshenker

    (Emory University School of Medicine)

  • Allan I. Levey

    (Emory University School of Medicine
    Emory University School of Medicine)

  • David J. Katz

    (Emory University School of Medicine)

Abstract

To investigate the mechanisms that maintain differentiated cells, here we inducibly delete the histone demethylase LSD1/KDM1A in adult mice. Loss of LSD1 leads to paralysis, along with widespread hippocampus and cortex neurodegeneration, and learning and memory defects. We focus on the hippocampus neuronal cell death, as well as the potential link between LSD1 and human neurodegenerative disease and find that loss of LSD1 induces transcription changes in common neurodegeneration pathways, along with the re-activation of stem cell genes, in the degenerating hippocampus. These data implicate LSD1 in the prevention of neurodegeneration via the inhibition of inappropriate transcription. Surprisingly, we also find that transcriptional changes in the hippocampus are similar to Alzheimer’s disease (AD) and frontotemporal dementia (FTD) cases, and LSD1 is specifically mislocalized to pathological protein aggregates in these cases. These data raise the possibility that pathological aggregation could compromise the function of LSD1 in AD and FTD.

Suggested Citation

  • Michael A. Christopher & Dexter A. Myrick & Benjamin G. Barwick & Amanda K. Engstrom & Kirsten A. Porter-Stransky & Jeremy M. Boss & David Weinshenker & Allan I. Levey & David J. Katz, 2017. "LSD1 protects against hippocampal and cortical neurodegeneration," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00922-9
    DOI: 10.1038/s41467-017-00922-9
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    Cited by:

    1. Beatriz del Blanco & Sergio Niñerola & Ana M. Martín-González & Juan Paraíso-Luna & Minji Kim & Rafael Muñoz-Viana & Carina Racovac & Jose V. Sanchez-Mut & Yijun Ruan & Ángel Barco, 2024. "Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Pengfei Guo & Nam Hoang & Joseph Sanchez & Elaine H. Zhang & Keshari Rajawasam & Kristiana Trinidad & Hong Sun & Hui Zhang, 2022. "The assembly of mammalian SWI/SNF chromatin remodeling complexes is regulated by lysine-methylation dependent proteolysis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Yi Liu & Brian Debo & Mingfeng Li & Zhennan Shi & Wanqiang Sheng & Yang Shi, 2021. "LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Cheng Zeng & Jiwei Chen & Emmalee W. Cooke & Arijita Subuddhi & Eliana T. Roodman & Fei Xavier Chen & Kaixiang Cao, 2023. "Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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