Fibronectin aggregation in multiple sclerosis.

Schaft, M.N. van der (2014) Fibronectin aggregation in multiple sclerosis. thesis, Medicine.

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Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Remyelination is necessary to rescue damaged axons and restore neural function. Although remyelination is generally observed in early stages of MS, it fails upon disease progression. Research has shown that fibronectin (Fn), an extracellular matrix protein, in the form of aggregates, can inhibit remyelination. Transient upregulation of Fn expression is a common response to tissue injury. However, in MS lesions reactive astrocytes cause Fn aggregation, which renders Fn resistant to degradation. This study was aimed to identify the mechanism that drives Fn aggregation. We hypothesized that integrin(s) on the astrocyte cell surface might play a role, since they mediate Fn fibrillogenesis, a physiological process by which an insoluble fibrillar matrix is formed out of Fn dimers. The local inflammatory response in MS was imitated using poly I:C, a TLR3 agonist. Immunoprecipitation and Western blot analysis did not reveal a significant effect of poly I:C stimulation on integrin αv expression in primary rat astrocytes. Immunocytochemistry seemed to show an altered expression of integrin subunits α5 and β1 of poly I:C stimulated cells, which was not confirmed by Western blot analysis. This might, however, indicate a potential role for integrin α5β1 in Fn aggregation, the integrin that initiates Fn fibrillogenesis. The role of integrins in Fn aggregation was further assessed by blocking integrin subunit β1 upon stimulation with poly I:C. This did not result in a decrease of Fn aggregation, possibly because poly I:C failed to induce Fn aggregation. Blocking of integrin subunits β3 and β5 independently of poly I:C showed no significant effect on Fn aggregation either. Concluding, our study did not provide evidence for a role of integrins in Fn aggregation. The mechanism underlying Fn aggregation remains subject of investigation. Uncovering this process is essential for developing means to disturb Fn aggregation in order to permit remyelination in MS.

Item Type:	Thesis (Thesis)
Supervisor name:	Baron, Dr. W. and Sikkema, Dr. A.H.
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:42
Last Modified:	25 Jun 2020 10:42
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/381

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