GM1-Ganglioside-Mediated Activation of the Unfolded Protein Response Causes Neuronal Death in a Neurodegenerative Gangliosidosis

Abstract

GM1-ganglioside (GM1) is a major sialoglycolipid of neuronal membranes that, among other functions, modulates calcium homeostasis. Excessive accumulation of GM1 due to deficiency of lysosomal beta-galactosidase (beta-gal) characterizes the neurodegenerative disease GM1-gangliosidosis, but whether the accumulation of GM1 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 GM1-gangliosidosis. GM1 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-/-/GalNAcT-/-, which do not accumulate GM1. These findings suggest that the UPR can be induced by accumulation of the sialoglycolipid GM1 and this causes a novel mechanism of neuronal apoptosis.

Gangliosides as apoptotic signals in ER stress response

“…7,47 Progress toward this endeavor has been made by generating mice with targeted disruptions of key genes that encode glycosyltransferases or glycosylhydrolases, the enzymes that control the synthesis and degradation of gangliosides. [48][49][50] Although no human diseases have yet been identified in which pathogenesis is attributed to genetic deficiency of any glycosyltransferase, the analyses of these genetically engineered null mice are beginning to identify the functions of complex gangliosides in development and cell differentiation.…”

“…A key player in this process is the cysteine protease caspase-12 whose transcription is induced during an ER stress response. 7,68,69 It has been postulated that caspase-12 contributes to cell death in ischemic brain and other neurodegenerative conditions, including Hungtington and Alzheimer disease. 69 Although the molecular pathways that link ER stress to caspase-12 induction are not fully elucidated, caspase-12 À/À cortical neurons are resistant to amyloid b-protein-mediated neurotoxicity (Figure 3).…”

“…However, recent studies have helped to add a piece to the puzzle that could eventually link the effects of ganglioside accumulation on the Ca 2 þ homeostasis and neurodegeneration. 7 Tessitore et al 7 demonstrated that in neurons of the GM1-gangliosidosis mouse model, excessive accumulation of GM1 in lysosomes results in the build-up of this ganglioside at the ER membrane, which in turn depletes ER Ca 2 þ stores and activates the ER stress response. The combined upregulation of BiP and CHOP increases the levels of processed ATF6 and activates JNK2 and caspase-12, which ultimately leads to neuronal apoptosis.…”

“…47,79 Ultimately, the disruption of intracellular Ca 2 þ homeostasis in ganglioside-accumulating cells could affect protein folding in the ER and induce the ER stress response through the conventional route, thereby suggesting a novel mechanism of neuronal apoptosis that could also occur in other neurodegenerative diseases. 7 …”

“…Under stress conditions that dramatically increase their intracellular concentration, gangliosides can initiate the induction of an apoptotic program. 7 Thus, a myriad of crucial cellular responses may be influenced or controlled by gangliosides and ultimately result in either cell growth and division, differentiation, or cell death. Nonetheless, the molecular mechanisms underlying many of these ganglioside-mediated responses remain largely unknown.…”