GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis

G(M1)-ganglioside (G(M1)) is a major sialoglycolipid of neuronal membranes that, among other functions, modulates calcium homeostasis. Excessive accumulation of Gm, due to deficiency of lysosomal beta-galactosidase (beta-gal) characterizes the neurodegenerative disease G(M1)-gangliosidosis, but whether the accumulation of G(M1) is directly responsible for CNS pathogenesis was unknown. Here we demonstrate that activation of an unfolded protein response (UPR) associated with the upregulation of BiP and CHOP and the activation of JNK2 and caspase-12 leads to neuronal apoptosis in the mouse model of G(M1)-gangliosidosis. Gm, loading of wild-type neurospheres recapitulated the phenotype of beta-gal(-/-) cells and activated this pathway by depleting ER calcium stores, which ultimately culminated in apoptosis. Activation of UPR pathways did not occur in mice double deficient for beta-gal and ganglioside synthase, beta-gal(-/-)/GaINAcT-/-, which do not accumulate G(M1). These findings suggest that the UPR can be induced by accumulation of the sialoglycolipid G(M1) and this causes a novel mechanism of neuronal apoptosis.