Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity

Alice Brockington; Ke Ning; Paul R. Heath; Elizabeth Wood; Janine Kirby; Nicoló Fusi; Neil D. Lawrence; Stephen B. Wharton; Paul G. Ince; Pamela J. Shaw

doi:10.1007/s00401-012-1058-5

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Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity

Alice Brockington, Ke Ning, Paul R. Heath, Elizabeth Wood, Janine Kirby, Nicoló Fusi, Neil D. Lawrence, Stephen B. Wharton, Paul G. Ince, Pamela J. Shaw

Acta Neuropathologica, 125(1), 2013.

Abstract

A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements and the function of external sphincters, with corresponding preservation of motor neurons in the brainstem oculomotor nuclei, and of Onuf\u2019s nucleus in the sacral spinal cord. Studying the differences in properties of neurons that are vulnerable and resistant to the disease process in ALS may provide insights into the mechanisms of neuronal degeneration, and identify targets for therapeutic manipulation. We used microarray analysis to determine the differences in gene expression between oculomotor and spinal motor neurons, isolated by laser capture microdissection from the midbrain and spinal cord of neurologically normal human controls. We compared these to transcriptional profiles of oculomotor nuclei and spinal cord from rat and mouse, obtained from the GEO omnibus database. We show that oculomotor neurons have a distinct transcriptional profile, with significant differential expression of 1,757 named genes ($q < 0.001$). Differentially expressed genes are enriched for the functional categories of synaptic transmission, ubiquitin-dependent proteolysis, mitochondrial function, transcriptional regulation, immune system functions, and the extracellular matrix. Marked differences are seen, across the three species, in genes with a function in synaptic transmission, including several glutamate and GABA receptor subunits. Using patch clamp recording in acute spinal and brainstem slices, we show that resistant oculomotor neurons show a reduced AMPA-mediated inward calcium current, and a higher GABA-mediated chloride current, than vulnerable spinal motor neurons. The findings suggest that reduced susceptibility to excitotoxicity, mediated in part through enhanced GABAergic transmission, is an important determinant of the relative resistance of oculomotor neurons to degeneration in ALS.

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BibTeX


@Article{Brockington-unravelling13,
  title = 	 {Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in {ALS} show distinct gene expression characteristics and decreased susceptibility to excitotoxicity},
  author = 	 {Brockington, Alice and Ning, Ke and Heath, Paul R. and Wood, Elizabeth and Kirby, Janine and Fusi, Nicoló and Lawrence, Neil D. and Wharton, Stephen B. and Ince, Paul G. and Shaw, Pamela J.},
  journal =      {Acta Neuropathologica},
  year = 	 {2013},
  volume = 	 {125},
  number =       {1},
  doi = 	 {10.1007/s00401-012-1058-5},
  pdf = 	 {http://link.springer.com/content/pdf/10.1007%2Fs00401-012-1058-5},
  url = 	 {/publications/brockington-unravelling13.html},
  abstract = 	 {A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements and the function of external sphincters, with corresponding preservation of motor neurons in the brainstem oculomotor nuclei, and of Onuf\u2019s nucleus in the sacral spinal cord. Studying the differences in properties of neurons that are vulnerable and resistant to the disease process in ALS may provide insights into the mechanisms of neuronal degeneration, and identify targets for therapeutic manipulation. We used microarray analysis to determine the differences in gene expression between oculomotor and spinal motor neurons, isolated by laser capture microdissection from the midbrain and spinal cord of neurologically normal human controls. We compared these to transcriptional profiles of oculomotor nuclei and spinal cord from rat and mouse, obtained from the GEO omnibus database. We show that oculomotor neurons have a distinct transcriptional profile, with significant differential expression of 1,757 named genes ($q < 0.001$). Differentially expressed genes are enriched for the functional categories of synaptic transmission, ubiquitin-dependent proteolysis, mitochondrial function, transcriptional regulation, immune system functions, and the extracellular matrix. Marked differences are seen, across the three species, in genes with a function in synaptic transmission, including several glutamate and GABA receptor subunits. Using patch clamp recording in acute spinal and brainstem slices, we show that resistant oculomotor neurons show a reduced AMPA-mediated inward calcium current, and a higher GABA-mediated chloride current, than vulnerable spinal motor neurons. The findings suggest that reduced susceptibility to excitotoxicity, mediated in part through enhanced GABAergic transmission, is an important determinant of the relative resistance of oculomotor neurons to degeneration in ALS.
}
}

Endnote

%0 Journal Article
%T Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity
%A Alice Brockington
%A Ke Ning
%A Paul R. Heath
%A Elizabeth Wood
%A Janine Kirby
%A Nicoló Fusi
%A Neil D. Lawrence
%A Stephen B. Wharton
%A Paul G. Ince
%A Pamela J. Shaw
%J Acta Neuropathologica
%D 2013	
%F Brockington-unravelling13
%R 10.1007/s00401-012-1058-5
%U /publications/brockington-unravelling13.html
%V 125
%N 1
%X A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements and the function of external sphincters, with corresponding preservation of motor neurons in the brainstem oculomotor nuclei, and of Onuf\u2019s nucleus in the sacral spinal cord. Studying the differences in properties of neurons that are vulnerable and resistant to the disease process in ALS may provide insights into the mechanisms of neuronal degeneration, and identify targets for therapeutic manipulation. We used microarray analysis to determine the differences in gene expression between oculomotor and spinal motor neurons, isolated by laser capture microdissection from the midbrain and spinal cord of neurologically normal human controls. We compared these to transcriptional profiles of oculomotor nuclei and spinal cord from rat and mouse, obtained from the GEO omnibus database. We show that oculomotor neurons have a distinct transcriptional profile, with significant differential expression of 1,757 named genes ($q < 0.001$). Differentially expressed genes are enriched for the functional categories of synaptic transmission, ubiquitin-dependent proteolysis, mitochondrial function, transcriptional regulation, immune system functions, and the extracellular matrix. Marked differences are seen, across the three species, in genes with a function in synaptic transmission, including several glutamate and GABA receptor subunits. Using patch clamp recording in acute spinal and brainstem slices, we show that resistant oculomotor neurons show a reduced AMPA-mediated inward calcium current, and a higher GABA-mediated chloride current, than vulnerable spinal motor neurons. The findings suggest that reduced susceptibility to excitotoxicity, mediated in part through enhanced GABAergic transmission, is an important determinant of the relative resistance of oculomotor neurons to degeneration in ALS.

RIS


TY  - JOUR
TI  - Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity
AU  - Alice Brockington
AU  - Ke Ning
AU  - Paul R. Heath
AU  - Elizabeth Wood
AU  - Janine Kirby
AU  - Nicoló Fusi
AU  - Neil D. Lawrence
AU  - Stephen B. Wharton
AU  - Paul G. Ince
AU  - Pamela J. Shaw
DA  - 2013/04/04	
ID  - Brockington-unravelling13
VL  - 125
IS  - 1
DO  - 10.1007/s00401-012-1058-5
L1  - http://link.springer.com/content/pdf/10.1007%2Fs00401-012-1058-5
UR  - /publications/brockington-unravelling13.html
AB  - A consistent clinical feature of amyotrophic lateral sclerosis (ALS) is the sparing of eye movements and the function of external sphincters, with corresponding preservation of motor neurons in the brainstem oculomotor nuclei, and of Onuf\u2019s nucleus in the sacral spinal cord. Studying the differences in properties of neurons that are vulnerable and resistant to the disease process in ALS may provide insights into the mechanisms of neuronal degeneration, and identify targets for therapeutic manipulation. We used microarray analysis to determine the differences in gene expression between oculomotor and spinal motor neurons, isolated by laser capture microdissection from the midbrain and spinal cord of neurologically normal human controls. We compared these to transcriptional profiles of oculomotor nuclei and spinal cord from rat and mouse, obtained from the GEO omnibus database. We show that oculomotor neurons have a distinct transcriptional profile, with significant differential expression of 1,757 named genes ($q < 0.001$). Differentially expressed genes are enriched for the functional categories of synaptic transmission, ubiquitin-dependent proteolysis, mitochondrial function, transcriptional regulation, immune system functions, and the extracellular matrix. Marked differences are seen, across the three species, in genes with a function in synaptic transmission, including several glutamate and GABA receptor subunits. Using patch clamp recording in acute spinal and brainstem slices, we show that resistant oculomotor neurons show a reduced AMPA-mediated inward calcium current, and a higher GABA-mediated chloride current, than vulnerable spinal motor neurons. The findings suggest that reduced susceptibility to excitotoxicity, mediated in part through enhanced GABAergic transmission, is an important determinant of the relative resistance of oculomotor neurons to degeneration in ALS.

ER  -

APA


Brockington, A., Ning, K., Heath, P.R., Wood, E., Kirby, J., Fusi, N., Lawrence, N.D., Wharton, S.B., Ince, P.G. & Shaw, P.J.. (2013). Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathologica 125(1) doi:10.1007/s00401-012-1058-5 Available from /publications/brockington-unravelling13.html.