Discipline of Medicine, Central Clinical School, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
Discipline of Child and Adolescent Health, Children's Hospital Westmead Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
Mol Neurobiol. 2021 May;58(5):2242-2255. doi: 10.1007/s12035-020-02244-2. Epub 2021 Jan 8.
Low orexin levels in the hypothalamus, and abnormal brainstem expression levels of many neurotransmitter and receptor systems in infants who died suddenly during a sleep period and diagnosed as sudden infant death syndrome (SIDS), may be linked to abnormal protein unfolding. We studied neuronal expression of the three unfolded protein response (UPR) pathways in the human infant brainstem, hypothalamus, and cerebellum: activating transcription factor 6 (ATF6), phosphorylated inositol-requiring enzyme 1 (IRE1), and phosphorylated protein-kinase (PKR)-like endoplasmic reticulum (ER) kinase (pPERK). Percentages of positively stained neurons were examined via immunohistochemistry and compared between SIDS (n = 28) and non-SIDS (n = 12) infant deaths. Further analysis determined the effects of the SIDS risk factors including cigarette smoke exposure, bed-sharing, prone sleeping, and an upper respiratory tract infection (URTI). Compared to non-SIDS, SIDS infants had higher ATF6 in the inferior olivary and hypoglossal nuclei of the medulla, higher pIRE1 in the dentate nucleus of the cerebellum, and higher pPERK in the cuneate nucleus and hypothalamus. Infants who were found prone had higher ATF6 in the hypoglossal and the locus coeruleus of the pons. Infants exposed to cigarette smoke had higher ATF6 in the vestibular and cuneate nuclei of the medulla. Infants who were bed-sharing had higher pPERK in the dorsal raphe nuclei of the pons and the Purkinje cells of the cerebellum. This study indicates that subgroups of SIDS infants, defined by risk exposure, had activation of the UPR in several nuclei relating to proprioception and motor control, suggesting that the UPR underlies the neuroreceptor system changes responsible for these physiological functions, leading to compromise in the pathogenesis of SIDS.
下丘脑的食欲素水平降低，以及在睡眠期间突然死亡并被诊断为婴儿猝死综合征（SIDS）的婴儿的脑干中许多神经递质和受体系统的异常表达水平，可能与异常蛋白质折叠有关。我们研究了人类婴儿脑干、下丘脑和小脑中三种未折叠蛋白反应（UPR）途径的神经元表达：激活转录因子 6（ATF6）、磷酸化肌醇需要酶 1（IRE1）和磷酸化蛋白激酶（PKR）样内质网（ER）激酶（pPERK）。通过免疫组织化学检查阳性染色神经元的百分比，并在 SIDS（n=28）和非 SIDS（n=12）婴儿死亡之间进行比较。进一步的分析确定了 SIDS 风险因素的影响，包括吸烟、同床、俯卧位睡眠和上呼吸道感染（URTI）。与非 SIDS 相比，SIDS 婴儿的延髓下橄榄核和舌下神经核中的 ATF6 更高，小脑齿状核中的 pIRE1 更高，楔束核和下丘脑中的 pPERK 更高。发现俯卧位的婴儿在桥脑的舌下神经核和蓝斑中有更高的 ATF6。暴露于香烟烟雾的婴儿在延髓的前庭核和楔束核中有更高的 ATF6。同床的婴儿在桥脑的中缝背核和小脑的浦肯野细胞中有更高的 pPERK。这项研究表明，根据风险暴露情况定义的 SIDS 婴儿亚组，在与本体感觉和运动控制有关的几个核中激活了 UPR，这表明 UPR 是导致这些生理功能的神经受体系统变化的基础，从而导致 SIDS 发病机制的损害。
