Molecular Neurobiology

, Volume 54, Issue 9, pp 7171–7185 | Cite as

Promotion of the Unfolding Protein Response in Orexin/Dynorphin Neurons in Sudden Infant Death Syndrome (SIDS): Elevated pPERK and ATF4 Expression

  • Nicholas J. Hunt
  • Karen A. Waters
  • Rita MachaalaniEmail author


We previously demonstrated that sudden infant death syndrome (SIDS) infants have decreased orexin immunoreactivity within the hypothalamus and pons compared to non-SIDS infants. In this study, we examined multiple mechanisms that may promote loss of orexin expression including programmed cell death, impaired maturation/structural stability, neuroinflammation and impaired unfolding protein response (UPR). Immunofluorescent and immunohistochemical staining for a number of markers was performed in the tuberal hypothalamus and pons of infants (1–10 months) who died from SIDS (n = 27) compared to age- and sex-matched non-SIDS infants (n = 19). The markers included orexin A (OxA), dynorphin (Dyn), cleaved caspase 3 (CC3), cleaved caspase 9 (CC9), glial fibrillary acid protein (GFAP), tubulin beta chain 3 (TUBB3), myelin basic protein (MBP), interleukin 1β (IL-1β), terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL), c-fos and the UPR activation markers: phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (pPERK), and activating transcription factor 4 (ATF4). It was hypothesised that pPERK and ATF4 would be upregulated in Ox neurons in SIDS compared to non-SIDS. Within the hypothalamus, OxA and Dyn co-localised with a 20 % decrease in expression in SIDS infants (P = 0.001). pPERK and ATF4 expression in OxA neurons were increased by 35 % (P = 0.001) and 15 % (P = 0.001) respectively, with linear relationships between the decreased OxA/Dyn expression and the percentages of co-localised pPERK/OxA and ATF4/OxA evident (P = 0.01, P = 0.01). No differences in co-localisation with CC9, CC3, TUNEL or c-fos, nor expression of MBP, TUBB3, IL-1β and GFAP, were observed in the hypothalamus. In the pons, there were 40 % and 20 % increases in pPERK expression in the locus coeruleus (P = 0.001) and dorsal raphe (P = 0.022) respectively; ATF4 expression was not changed. The findings that decreased orexin levels in SIDS infants may be associated with an accumulation of pPERK suggest decreased orexin translation. As pPERK may inhibit multiple neuronal groups in the pons in SIDS infants, it could also indicate that a common pathway promotes loss of protein expression and impaired functionality of multiple brainstem neuronal groups.


UPR ATF4 CREB Development Sleep Hypocretin 



Third ventricle


Activating transcription factor 4


Binding immunogen protein


Cleaved caspase 3


Cleaved caspase 9


CCAAT-enhancer-binding protein homologous protein


Deionised water


Dorsal medial hypothalamus


Dorsal raphe




Endoplasmic reticulum


Glial fibrillary acid protein






Interleukin 1-beta


Locus coeruleus


Lateral hypothalamus




Myelin basic protein


Normal horse serum




Orexin A


Phosphate-buffered saline


Perifornical area


Phosphorylated protein kinase RNA-like endoplasmic reticulum kinase




Rapid eye movement


Sudden infant death syndrome


Tuberal hypothalamus


Tubulin beta chain 3


Terminal deoxynucleotidyl transferase dUTP nick-end labelling


Unfolding protein response


Upper respiratory tract infections



The tissue used in this study was obtained from the NSW Forensic and Analytical Science Service. The authors acknowledge the facilities and scientific and technical assistance of the Australian Microscopy and Microanalysis Research Faculty at the Australian Centre of Microscopy and Micro Analysis, University of Sydney.

Compliance with Ethical Standards


This research was funded by the SIDS Stampede, Australia, and the Miranda Belshaw Foundation.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12035_2016_234_MOESM1_ESM.docx (27 kb)
Supplementary Table 1 (DOCX 27 kb)
12035_2016_234_MOESM2_ESM.docx (33 kb)
Supplementary Table 2 (DOCX 33 kb)
12035_2016_234_Fig7_ESM.gif (447 kb)
Supplementary Figure 1

Changes in OxA, Dyn, CC3 and TUNEL (TUN) in the nuclei and regions of the tuberal hypothalamus (THT). No changes in CC3 or TUN were observed in any nuclei or levels of the THT between non-SIDS and SIDS cases. Decreased expression was observed overall in the anterior THT (OxA: F 1,7 = 6.75, P = 0.036; Dyn: F 1,7 = 6.75, P = 0.036), and within the PeF, LH and overall of the central THT (OxA: F 1,23 = 9.78, 10.79, 14.16; P = 0.005, 0.003, 0.001; Dyn: F 1,23 = 10.54, 6.23, 12.44; P = 0.004, 0.02, 0.001) and posterior THT (OxA: F 1,10 = 6.44, 12.94, 21.00; P = 0.034, 0.005, 0.001; Dyn: F 1,10 = 5.82, 9.64, 23.00; P = 0.044, 0.011, 0.001). (GIF 446 kb)

12035_2016_234_MOESM3_ESM.tif (12.1 mb)
High resolution image (TIFF 12385 kb)
12035_2016_234_Fig8_ESM.gif (121 kb)
Supplementary Figure 2

No differences in Ox neuron size (a–c) or total THT neuronal numbers (d–f) between non-SIDS and SIDS infants within the anterior, central or posterior THT. (GIF 120 kb)

12035_2016_234_MOESM4_ESM.tif (9.8 mb)
High resolution image (TIFF 10053 kb)
12035_2016_234_Fig9_ESM.gif (73 kb)
Supplementary Figure 3

Co-localisation of c-fos and OxA was not different between non-SIDS and SIDS infants. (a) non-SIDS and (b) SIDS expression staining images, OxA staining was observed in the cytoplasm of neurons and c-fos expression in the nucleus. (c) box and whisker plot comparing non-SIDS and SIDS co-localised c-fos/OxA expression. (GIF 73 kb)

12035_2016_234_MOESM5_ESM.tif (6.5 mb)
High resolution image (TIFF 6692 kb)
12035_2016_234_Fig10_ESM.gif (158 kb)
Supplementary Figure 4

(GIF 158 kb)

12035_2016_234_MOESM6_ESM.tif (5.3 mb)
High resolution image (TIFF 5395 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Nicholas J. Hunt
    • 1
    • 2
  • Karen A. Waters
    • 1
    • 2
    • 3
  • Rita Machaalani
    • 1
    • 2
    • 3
    Email author
  1. 1.SIDS and Sleep Apnoea Laboratory, Department of Medicine, Sydney Medical SchoolUniversity of SydneySydneyAustralia
  2. 2.BOSCH Institute of Biomedical ResearchUniversity of SydneySydneyAustralia
  3. 3.The Children’s HospitalWestmeadAustralia

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