During normal brain development, axons are myelinated by mature oligodendrocytes 
(OLGs). Under pathological, demyelinating conditions within the central nervous 
system (CNS), axonal remyelination is only partially successful because 
oligodendrocyte precursor cells (OPCs) largely remain in an undifferentiated 
state resulting in a failure to generate myelinating OLGs. Tissue 
Transglutaminase (TG2) is a multifunctional enzyme, which amongst other 
functions, is involved in cell differentiation. Therefore, we hypothesized that 
TG2 contributes to differentiation of OPCs into OLGs and thereby stimulates 
remyelination. In vivo studies, using the cuprizone model for de- and 
remyelination in TG2(-/-) and wild-type mice, showed that during remyelination 
expression of proteolipid protein mRNA, as a marker for remyelination, in the 
corpus callosum lags behind in TG2(-/-) mice resulting in less myelin formation 
and, moreover, impaired recovery of motor behavior. Subsequent in vitro studies 
showed that rat OPCs express TG2 protein and activity which reduces when the 
cells have matured into OLGs. Furthermore, when TG2 activity is 
pharmacologically inhibited, the differentiation of OPCs into myelin-forming 
OLGs is dramatically reduced. We conclude that TG2 plays a prominent role in 
remyelination of the CNS, probably through stimulating OPC differentiation into 
myelin-forming OLGs. Therefore, manipulating TG2 activity may represent an 
interesting new target for remyelination in demyelinating diseases.