Pathogenesis of inclusion bodies in (CAG)(n)/Q(n)-expansion diseases with special reference to the role of tissue transglutaminase and to selective vulnerability

At least eight neurodegenerative diseases, including Huntington disease, ar e caused by expansions in (CAG)(n) repeats in the affected gene and by an i ncrease in the size of the corresponding polyglutamine domain in the expres sed protein. A hallmark of several of these diseases is the presence of abe rrant, proteinaceous aggregates in the nuclei and cytosol of affected neuro ns. Recent studies have shown that expanded polyglutamine (Q(n)) repeats ar e excellent glutaminyl-donor substrates of tissue transglutaminase, and tha t the substrate activity increases with increasing size of the polyglutamin e domain. Tissue transglutaminase is present in the cytosol and nuclear fra ctions of brain tissue. Thus, the nuclear and cytosolic inclusions in Hunti ngton disease may contain tissue transglutaminase-catalyzed covalent aggreg ates. The (CAG)(n)/Q(n)-expansion diseases are classic examples of selectiv e vulnerability in the nervous system, in which certain cells/structures ar e particularly susceptible to toxic insults. Quantitative differences in th e distribution of the brain transglutaminase(s) and its substrates, and in the activation mechanism of the brain transglutaminase(s), may explain in p art selective vulnerability in a subset of neurons in (CAG)(n)-expansion di seases, and possibly in other neurodegenerative disease. If tissue transglu taminase is found to be essential for development of pathogenesis, then inh ibitors of this enzyme may be of therapeutic benefit.