LSD1 protects against hippocampal and cortical neurodegeneration

Michael A. Christopher, Dexter A. Myrick, Benjamin G. Barwick, Amanda K. Engstrom, Kirsten A. Porter-Stransky, Jeremy M. Boss, David Weinshenker, Allan I. Levey and David J. Katz ()
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Michael A. Christopher: Emory University School of Medicine
Dexter A. Myrick: Emory University School of Medicine
Benjamin G. Barwick: Emory University
Amanda K. Engstrom: Emory University School of Medicine
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
David J. Katz: Emory University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00922-9

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