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  • We postulate that OT contained


    We postulate that OT contained in milk during early postnatal development causes a mild enteroprotective preconditioning of the ER (Fig 9). This is perhaps akin to a mechanism shown by others [50], [51], [52], which is characterized by selective activation of the IRE1a/XBP1/eIF2a (via PKR) UPR pathway. As aforementioned, OTR Chlormezanone peaks at a critical time during initial gut exposure to colonizing bacteria during the milk suckling period. We speculate that during this period, OT may confer a survival advantage by limiting inflammation and its effects on permeability, motility and mucosal integrity, functions found to be impaired in OTR deficient mice [6]. Abnormal gut permeability has been implicated in aberrant development resulting in an autism-like phenotype in an animal model [53]. Moreover, infants that are breastfed in the early postnatal period, especially those ingesting colostrum, have a reduced risk for autism spectrum disorders [54], [55]. Our results, when considered in context with this evidence, strongly imply that OT in milk confers protection against first exposure to bacteria and other proteins in the newborn gut.
    Acknowledgments We are grateful to Chris Heger, PhD of ProteinSimple, Inc. for his expertise and assistance with the automated immunocapillary electrophoresis and its description in this manuscript. Funding for this project was provided by the Einhorn Family Charitable Trust and the Fleur Fairman Family to the Nurture Science Program at Columbia University Medical Center. Funding in part was also provided by Columbia University's CTSA from NCRR/NIH (UL1RR024156). The study sponsors had no role in the conduct of the study, the interpretation of data or the drafting of this article. Author MMM received salary support from the New York State Office of Mental Health research scientist position. The authors have no competing financial interests.
    Introduction Sigma-1 receptor subtype (σ1R) density is decreased in the nigrostriatal motor system of Parkinson's disease (PD) patients (Mishina et al., 2005). Numerous studies have reported the presence of movement disorder in σ1R knockout mice (σ1R−/− mice) (Bernard-Marissal et al., 2015, Mavlyutov et al., 2010). The movement deficits in σ1R−/− mice have been associated with the degeneration of motor neuron in spinal cord (Bernard-Marissal et al., 2015). Adult σ1R−/− mice present motor coordination and balance disabilities as measured by evaluation of rotarod test (Hong et al., 2015, Mavlyutov et al., 2010). Immunohistochemical staining has demonstrated the localization of σ1R protein in the dopaminergic neurons of substantia nigra pars compacta (SNpc) (Alonso et al., 2000). However, the influence of σ1R deficiency in dopaminergic neurons has not yet been reported. The σ1R is highly expressed in a subdomain of the endoplasmic reticulum (ER), which plays an important role in the ER-mitochondrial interorganelle calcium signaling (Hayashi and Su, 2007). The σ1R dysfunction occurs via disturbed ER-mitochondria contacts, affects intracellular calcium signaling, and induces the activation of ER stress (Bernard-Marissal et al., 2015). ER chaperones not only facilitate the proper folding of newly synthesized proteins but also prevent the accumulation of misfolded proteins by designating them for ER-related degradation. Furthermore, the knockdown of σ1R in the NSC34 cell line induces the misfolded protein response followed by the inhibition of the ubiquitin proteasome system and cell death (Prause et al., 2013). Colla et al. (2012) have demonstrated that α-synuclein (αSyn) oligomers start to accumulate in the ER through an interaction with ER chaperones. The decreased degradation of αSyn that leads to the accumulation and aggregation of αSyn is believed to play a critical role in the pathogenesis of Lewy bodies (Dikiy and Eliezer, 2012). Approximately, 90% of αSyn that is present in Lewy bodies is phosphorylated at Ser129 (Anderson et al., 2006, Fujiwara et al., 2002). The silencing of σ1R function increases the number of nuclear inclusions and causes accumulation of mutant huntingtin (Miki et al., 2015). The oligomerization, aggregation, and even deposition of αSyn are neurotoxic (Connor-Robson et al., 2016, Periquet et al., 2007, Sharon et al., 2003).