PAK3 downregulation induces cognitive impairment following cranial irradiation

Author:

Lee Haksoo1ORCID,Kang Hyunkoo1,Moon Changjong2ORCID,Youn BuHyun134ORCID

Affiliation:

1. Department of Integrated Biological Science, Pusan National University

2. Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University

3. Department of Biological Sciences, Pusan National University

4. Nuclear Science Research Institute, Pusan National University

Abstract

Cranial irradiation is used for prophylactic brain radiotherapy as well as the treatment of primary brain tumors. Despite its high efficiency, it often induces unexpected side effects, including cognitive dysfunction. Herein, we observed that mice exposed to cranial irradiation exhibited cognitive dysfunction, including altered spontaneous behavior, decreased spatial memory, and reduced novel object recognition. Analysis of the actin cytoskeleton revealed that ionizing radiation (IR) disrupted the filamentous/globular actin (F/G-actin) ratio and downregulated the actin turnover signaling pathway p21-activated kinase 3 (PAK3)-LIM kinase 1 (LIMK1)-cofilin. Furthermore, we found that IR could upregulate microRNA-206–3 p (miR-206–3 p) targeting PAK3. As the inhibition of miR-206–3 p through antagonist (antagomiR), IR-induced disruption of PAK3 signaling is restored. In addition, intranasal administration of antagomiR-206–3 p recovered IR-induced cognitive impairment in mice. Our results suggest that cranial irradiation-induced cognitive impairment could be ameliorated by regulating PAK3 through antagomiR-206–3 p, thereby affording a promising strategy for protecting cognitive function during cranial irradiation, and promoting quality of life in patients with radiation therapy.

Funder

Pusan National University

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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