The unfolded protein response (UPR) is implicated in many neurodegenerative disorders including Alzheimer, Parkinson and prion diseases, and the leukodystrophy, Pelizaeus-Merzbacher disease (PMD). Critical features of degeneration in several of these diseases involve activation of cell death pathways in various neural cell populations, and the initiator caspase 12 has been proposed to play a central role. Accordingly, pharmacological strategies to inhibit caspase 12 activity have received remarkable attention in anticipation of effecting disease amelioration. Our investigation in animal models of PMD demonstrates that caspase 12 is activated following accumulation of mutant proteins in oligodendrocytes; however, eliminating caspase 12 activity does not alter pathophysiology with respect to levels of apoptosis, oligodendrocyte function, disease severity or life span. We conclude that caspase 12 activation by UPR signaling is an epiphenomenon that plays little discernable role in the loss of oligodendrocytes in vivo and may portend the inconsequence of caspase 12 to the pathophysiology of other protein conformational diseases.