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The Unfolded Protein Response in the Human Infant Brain and Dysregulation Seen in Sudden Infant Death Syndrome (SIDS)

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Abstract

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.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Notes

  1. This study’s cohort differs to our previous one utilised by Hunt et al. [5] in that we have 7 fewer non-SIDS cases and one extra SIDS case as not all non-SIDS cases had a medulla section available at the correct mid to rostral level. Analyses for pPERK in the hypothalamus and the pons were run using the values obtained by Hunt et al. [5] but restricted to the cases in this study.

Abbreviations

AN:

Arcuate nucleus

ATF6:

Activating transcription factor 6

C/EBP:

CCAAT/enhancer binding protein

CHOP:

C/EBP homologous protein

CUN:

Cuneate nucleus

DAB:

3,3′-Diaminobenzidine

DMNV:

Dorsal motor nucleus of the vagus

DN:

Dentate nucleus

DR:

Dorsal raphe nucleus

ER:

Endoplasmic reticulum

FFPE:

Formalin-fixed paraffin-embedded

GABA:

γ-Aminobutyric acid

GC:

Golgi cells

GL:

Granular layer

IHC:

Immunohistochemistry

ION:

Inferior olivary nucleus

IRE1:

Inositol-requiring enzyme 1

LC:

Locus coeruleus

ML:

Molecular layer

NBT/BCIP:

Nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl

NHS:

Normal horse serum

NMDA:

N-methyl-D-aspartate

NTS:

Nucleus tractus solitarius

OxA:

Orexin isoform A

PN:

Pontine nucleus

pPERK:

Phosphorylated protein kinase (PKR)-like ER kinase

PC:

Purkinje cells

SIDS:

Sudden infant death syndrome

UPR:

Unfolded protein response

URTI:

Upper respiratory tract infection

VEST:

Vestibular nucleus

XII:

Hypoglossal nucleus

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Acknowledgements

The tissue used in this study was obtained from the NSW Forensic and Analytical Science Service. We acknowledge Dr. Arunnjah Vivekanandarajah who undertook the tissue collecting on slides.

Funding

ST was supported by a scholarship partly funded by philanthropy from the parents of Grant Stone (who died of SIDS) in his honour.

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Authors and Affiliations

  1. 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

    Shannon Thomson, Karen A. Waters & Rita Machaalani

  2. 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

    Karen A. Waters & Rita Machaalani

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  1. Shannon Thomson
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Contributions

ST ran experiments, performed data analyses, and wrote the manuscript. RM conceived the project, directed, and overlooked it, including analysis and manuscript drafting. KW contributed to manuscript drafting and clinical insight.

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Correspondence to Rita Machaalani.

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Ethical approval was from the NSW Health RPAH Zone (X13-0038 and 599 HREC/13/RPAH/54) and University of Sydney Ethic committees.

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The need to obtain participant consent was waived as per our ethics approval due to the post-mortem nature of this study. Moreover, all included cases were de-identified.

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Thomson, S., Waters, K.A. & Machaalani, R. The Unfolded Protein Response in the Human Infant Brain and Dysregulation Seen in Sudden Infant Death Syndrome (SIDS). Mol Neurobiol 58, 2242–2255 (2021). https://doi.org/10.1007/s12035-020-02244-2

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  • DOI: https://doi.org/10.1007/s12035-020-02244-2

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