SUPERACTIVATION OF TRANSGLUTAMINASE TYPE-2 WITHOUT CHANGE IN ENZYME LEVEL OCCURS DURING PROGRESSIVE NEURODEGENERATION IN THE MND MOUSE MUTANT

We have investigated the activity of the Ca2+-dependent apoptosis-rela ted enzyme transglutaminase type 2 in the mnd/mnd mouse mutant. Transg lutaminase activity in mnd/mnd central nervous system (CNS) tissue hom ogenates was identical to that of healthy animals at 3 months of age, but at 8 months it was greater in the mnd/mnd CNS by up to four times, depending on the region. Western blot analysis showed no difference i n the level of immunoreactive transglutaminase type 2 in spinal cord h omogenates between mnd/mnd and healthy mice. However, a greater number of acyl donor protein substrates of transglutaminase were identified in mnd/mnd tissue. N-epsilon(gamma-Glutamyl)lysine cross linked produc t of transglutaminase activity was localized to the soma of degenerati ng motor neurons in the mnd/mnd mouse spinal cord. We conclude that ne urodegeneration in the mnd/mnd mouse is accompanied by activation of t ransglutaminase at substrate level. Possible mechanisms of activation and its implications for cellular pathology are discussed.