Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder
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ORIGINAL PAPER
Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder Koichi Kawada1 · Seisuke Mimori2
Received: 26 April 2017 / Revised: 23 July 2017 / Accepted: 29 July 2017 © Springer Science+Business Media, LLC 2017
Abstract Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress. The inhibition of neurite outgrowth and expression of synaptic factors are observed in ASD. Similarly, ER stress suppresses the neurite outgrowth and expression of synaptic factors. Additionally, hyperplasia of the brain is observed in patients with ASD. ER stress also enhances neuronal differentiation. Synaptic factors, such as cell adhesion molecule and shank, play important roles in the formation of neural circuits. Thus, ER stress is associated with the abnormalities of neuronal differentiation, neurite outgrowth, and synaptic protein expression. ER stress elevates the expression of the ubiquitin-protein ligase HRD1 for the degradation of unfolded proteins. HRD1 expression significantly increased * Koichi Kawada [email protected] Seisuke Mimori [email protected] 1
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15‑8 Shiomi‑cho, Choshi, Chiba 288‑0025, Japan
2
Department of Clinical Medicine, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba 288‑0025, Japan
in the middle frontal cortex in the postmortem of patients with ASD. Moreover, HRD1 silencing improved the abnormalities induced by ER stress. Because other ubiquitin ligases are related with neurite outgrowth, ER stress may be related to the pathogenesis of neuronal developmental diseases via abnormalities of neuronal differentiation or maturation. Keywords Endoplasmic reticulum stress · Autism spectrum disorder · Neurite outgrowth · Neuronal differentiation · Ubiquitin ligase HRD1
Introduction Autism spectrum disorder (ASD) is classified as neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. It is characterized by defective development and congenital dysfunction of the central nervous system (CNS) and marked by “impaired social interaction,” “verbal developmental retardation,” and “restricted and repetitive behavior.” Recently, several hypotheses have been proposed to explain the pathogenic mechanism underlying ASD, which included segmental duplication and a gene mutation of chromosome 15q11–q13 [1], which is known as the genomi
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