Activation of the Unfolded Protein Response in myelinating rat cerebellar tracts
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1
National University of Ireland, Galway, Galway Neuroscience Centre, Ireland
The development of white matter tracts requires a dramatic increase of lipid and protein synthesis in oligodendrocytes to produce myelin. The endoplasmic reticulum (ER) is the primary site of synthesis for membranous proteins and lipids. We hypothesise that the Unfolded Protein Response (UPR) is activated in oligodendrocytes in order to expand ER capacity and facilitate myelination. Chromogenic immunohistochemistry was used to characterise myelin development in the rat cerebellum. ER stress signalling was detected using antibodies for activated UPR transducers (pIRE1, ATF6 and pPERK) and associated downstream molecules (peIF2alpha, XBP1, PDI, GRP78, GRP94, CHOP and calreticulin). The density of positive cells in developing white matter tracts was blindly assessed and normalised to the mean cell density of each age to account for white matter expansion.
Nuclear staining for ATF6 (indicative of the active transcription factor) peaked at P10 (p<0.01), concurrent with early myelination. This was matched by an increase in non-nuclear (inactive) stained cells at later timepoints (p<0.05). Positive cells for activated IRE1 were widespread at P14 and P17 vs P7 and adult (p<0.05, p<0.01). Downstream targets of the UPR were all significantly upregulated at P17 (vs P7 p<0.01, p<0.001, p<0.01 for GRP78, GRP94 and PDI respectively), and remained significantly elevated in adult tissue. Expression levels of pPERK and associated molecules were negligible. Expression of ER-associated molecules was observed in dual-labelled olig2-positive cells in developing white matter tracts.
To our knowledge, this is the first demonstration of the activated UPR in developing white matter. This data may have implications for mechanisms underlying remyelination for disorders such as multiple sclerosis.
Acknowledgements
Grant support from the Health Research Board and Multiple Sclerosis Ireland (MRCG/2011/21) is gratefully acknowledged. Dr. McMahon is supported by the NUIG Foundation Office.
Keywords:
Myelination,
Endoplasmic Reticulum Stress,
oligodendrocytes,
unfolded protein response (UPR),
er stress,
ATF6,
IRE1,
pperk
Conference:
Neuroscience Ireland Young Neuroscientists Symposium 2014 , Dublin, Ireland, 20 Sep - 20 Sep, 2014.
Presentation Type:
Poster Presentation
Topic:
Early Career Neuroscience
Citation:
Naughton
M,
McMahon
J and
FitzGerald
U
(2014). Activation of the Unfolded Protein Response in myelinating rat cerebellar tracts.
Front. Neurosci.
Conference Abstract:
Neuroscience Ireland Young Neuroscientists Symposium 2014 .
doi: 10.3389/conf.fnins.2014.87.00037
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Received:
17 Sep 2014;
Published Online:
17 Sep 2014.
*
Correspondence:
Ms. Michelle Naughton, National University of Ireland, Galway, Galway Neuroscience Centre, Galway, Ireland, michelle.naughton1@gmail.com