Abstract
Astrogliosis as seen in Multiple Sclerosis (MS) develops into astroglial scarring, which is beneficial because it seals off the site of central nervous system (CNS) damage. However, astroglial scarring also forms an obstacle that inhibits axon outgrowth and (re)myelination in brain lesions. This is possibly an important cause for incomplete remyelination in the CNS of early stage MS patients and for failure in remyelination when the disease progresses. In this study we address whether under demyelinating conditions in vivo, tissue Transglutaminase (TG2), a Ca2+ -dependent enzyme that catalyses posttranslational modification of proteins, contributes to extracellular matrix (ECM) deposition and/or aggregation. We used the cuprizone model for de- and remyelination. TG2 immunoreactivity and enzymatic activity time-dependently appeared in astrocytes and ECM, respectively, in the corpus callosum of cuprizone-treated mice. Enhanced presence of soluble monomeric and multimeric fibronectin was detected during demyelination, and fibronectin immunoreactivity was slightly decreased in cuprizone-treated TG2−/− mice. In vitro TG2 overexpression in astrocytes coincided with more, while knock-down of TG2 with less fibronectin production. TG2 contributes, at least partly, to fibronectin production, and may play a role in fibronectin deposition during cuprizone-induced demyelination. Our observations are of interest in understanding the functional implications of TG2 during astrogliosis.
Highlights
Multiple Sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the human central nervous system (CNS) that mainly affects young adults between 20 years and 40 years of age[1,2]
The model was validated by studying de-and remyelination, as well as astrogliosis and microglial activation by myelin proteolipid protein (PLP), glial fibrillary acidic protein (GFAP) and Mac-3 immunohistochemistry, respectively
In the present study we showed that during demyelination, TG2 immunoreactivity and enzymatic activity time-dependently appear in astrocytes and extracellular matrix (ECM) in the corpus callosum of mice treated with cuprizone
Summary
Multiple Sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the human central nervous system (CNS) that mainly affects young adults between 20 years and 40 years of age[1,2]. In chronically demyelinated MS lesions, clear deposition of ECM proteins, including fibronectin and laminin has been observed[40,41,42] Under these conditions, fibronectin inhibits (re)myelination[42], whereas laminin is a myelination permissive extracellular matrix molecule[43,44]. Cuprizone is a copper chelator that is given orally to mice and results in varying degrees of oligodendroglial damage and demyelination in the CNS45,46 This model might be an appropriate model for studying chronic pathology in MS, since demyelination in this model is accompanied by a strong astrogliosis and microgliosis, as seen in MS patients[47]. This model, does not show the disturbance of the blood-brain barrier as seen in MS and is without a profound influx of immune cells[46,48,49], comparable to the hypocellular character of chronic, demyelinated MS lesions[50]
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