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

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

iScience. 2022 Jan 25;25(2):103814. doi: 10.1016/j.isci.2022.103814. eCollection 2022 Feb 18.

Authors

Stacey L Peek^{1

2

3}, Peter J Bosch^{2

3}, Ethan Bahl^{3

4

5}, Brianna J Iverson^{2

3}, Mrutyunjaya Parida^{2

6

7}, Preeti Bais⁸, J Robert Manak^{2

6

7}, Jacob J Michaelson^{3

5

9

10

11}, Robert W Burgess⁸, Joshua A Weiner^{2

3

5}

Affiliations

¹ Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242, USA.
² Department of Biology, University of Iowa, Iowa City, IA 52242, USA.
³ Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA.
⁴ Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA.
⁵ Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
⁶ Departments of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
⁷ Roy J. Carver Center for Genomics, University of Iowa, Iowa City, IA 52242, USA.
⁸ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
⁹ Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, IA 52242, USA.
¹⁰ Department of Communication Sciences and Disorders, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA.
¹¹ Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA 52242, USA.

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.

Keywords: biological sciences; cell biology; molecular biology; neuroscience.

Abstract

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