p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

Stacey L. Peek; Peter J. Bosch; Ethan Bahl; Brianna J. Iverson; Mrutyunjaya Parida; Preeti Bais; J. Robert Manak; Jacob J. Michaelson; Robert W. Burgess; Joshua A. Weiner

doi:10.1016/j.isci.2022.103814

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p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

Journal article

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p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2

Stacey L. Peek, Peter J. Bosch, Ethan Bahl, Brianna J. Iverson, Mrutyunjaya Parida, Preeti Bais, J. Robert Manak, Jacob J. Michaelson, Robert W. Burgess and Joshua A. Weiner

iScience, Vol.25(2), p.103814

02/01/2022

DOI: 10.1016/j.isci.2022.103814

PMCID: PMC8844820

PMID: 35198879

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Abstract

Proper gene regulation is critical for both neuronal development and maintenance as the brain matures. We previously demonstrated that Akirin2, an essential nuclear protein that interacts with transcription factors and chromatin remodeling complexes, is required for the embryonic formation of the cerebral cortex. Here we show that Akirin2 plays a mechanistically distinct role in maintaining healthy neurons during cortical maturation. Restricting Akirin2 loss to excitatory cortical neurons resulted in progressive neurodegeneration via necroptosis and severe cortical atrophy with age. Comparing transcriptomes from Akirin2-null postnatal neurons and cortical progenitors revealed that targets of the tumor suppressor p53, a regulator of both proliferation and cell death encoded by Trp53, were consistently upregulated. Reduction of Trp53 rescued neurodegeneration in Akirin2-null neurons. These data: (1) implicate Akirin2 as a critical neuronal maintenance protein, (2) identify p53 pathways as mediators of Akirin2 functions, and (3) suggest Akirin2 dysfunction may be relevant to neurodegenerative diseases.

Biological Sciences

Cell Biology

Molecular Biology

Neuroscience

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Title: Subtitle: p53-mediated neurodegeneration in the absence of the nuclear protein Akirin2
Creators: Stacey L. Peek - Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA; Department of Biology, University of Iowa, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA
Peter J. Bosch - Department of Biology, University of Iowa, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA
Ethan Bahl - Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Brianna J. Iverson - Department of Biology, University of Iowa, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA
Mrutyunjaya Parida - Department of Biology, University of Iowa, Iowa City, IA 52242, USA; Departments of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; Roy J. Carver Center for Genomics, University of Iowa, Iowa City, IA 52242, USA
Preeti Bais - The Jackson Laboratory, Bar Harbor, ME 04609, USA
J. Robert Manak - Department of Biology, University of Iowa, Iowa City, IA 52242, USA; Departments of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; Roy J. Carver Center for Genomics, University of Iowa, Iowa City, IA 52242, USA
Jacob J. Michaelson - Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, IA 52242, USA; Department of Communication Sciences and Disorders, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA; Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA 52242, USA
Robert W. Burgess - The Jackson Laboratory, Bar Harbor, ME 04609, USA
Joshua A. Weiner - Department of Biology, University of Iowa, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Corresponding author
Resource Type: Journal article
Publication Details: iScience, Vol.25(2), p.103814
DOI: 10.1016/j.isci.2022.103814
PMID: 35198879
PMCID: PMC8844820
NLM abbreviation: iScience
ISSN: 2589-0042
eISSN: 2589-0042
Publisher: Elsevier
Grant note: DOI: 10.13039/100011641, name: The University of Iowa Office of the Vice President for Research
Language: English
Date published: 02/01/2022
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Communication Sciences and Disorders; Liberal Arts and Science Admin; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984216659902771

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