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Characterization of molecular alterations in normal appearing white matter of multiple sclerosis brain tissue and its animal model experimental autoimmune encephalomyelitis

Zeis, Thomas. Characterization of molecular alterations in normal appearing white matter of multiple sclerosis brain tissue and its animal model experimental autoimmune encephalomyelitis. 2008, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8745

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Abstract

Multiple sclerosis is a chronic, inflammatory and demyelinating disease of the CNS.
Although diffuse inflammatory damage as well as progressive axonal injury has been
shown in the chronic phase of the disease, little is known about the molecular
mechanisms underlying these pathological processes. In order to identify such
mechanisms, the gene expression profile in MS normal appearing white matter
(NAWM), was studied. Furthermore, the presence of such changes in a MS animal
model was analyzed.
A differential gene expression analysis on NAWM revealed the upregulation of genes
involved in anti-inflammatory mechanisms, such as STAT6, and genes involved in
pro-inflammatory mechanisms, such as STAT4. By immunohistochemistry, a
predominant expression of the components of the STAT6 signalling pathway in
oligodendrocytes was demonstrated. These findings suggest an endogenous
inflammatory activation throughout the whole MS NAWM, in which oligodendrocytes
actively participate. Whether such changes represent also earliest pathological
processes in MS or are due to a long, chronic disease course is unknown. Therefore,
differential gene expression of a biopsy with NAWM taken from a 17 year-old woman
during her first clinical incident was analyzed. This revealed a strong upregulation of
neuronal nitric oxide synthase (nNOS) as well as STAT6, and genes involved in
neuroprotection against oxidative stress. These findings suggest that intrinsic
inflammatory- as well as neuroprotective mechanism activation are early events in MS NAWM, which sustain over time. To study these mechanisms in more detail, a
gene expression study in an animal model for MS was performed. For this, normal
appearing white and grey matter of DA rats with recombinant MOG-induced EAE was
analyzed. However, an induction of immune-modulating or neuroprotective genes
was not evident in EAE NAWM. Therefore, we conclude that MOG-induced EAE in
DA rat may not be a suitable model to investigate the immune-modulating or
neuroprotective mechanisms observed in MS NAWM. In contrast, a comparable
downregulation of glutamate receptors and genes encoding mitochondrial proteins as
in MS NAGM was detected in EAE NAGM.
In summary, gene expression changes characteristic of endogenous inflammatory as
well as neuroprotective mechanisms were identified in the MS NAWM, whereas
these mechanisms were not present in an animal model of this disease, leading to
the conclusion that in MS intrinsic mechanisms may take place, independent of
acute, autoimmune-mediated inflammation.
Advisors:Reichert, Heinrich
Committee Members:Schaeren-Wiemers, Nicole and Rüegg, Markus A.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Molecular Zoology (Reichert)
UniBasel Contributors:Zeis, Thomas and Reichert, Heinrich and Schaeren-Wiemers, Nicole and Rüegg, Markus A.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8745
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:196
Language:English
Identification Number:
Last Modified:22 Apr 2018 04:30
Deposited On:02 Dec 2009 13:21

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