Ursodeoxycholic Acid Binds PERK and Ameliorates Neurite Atrophy in a Cellular Model of GM2 Gangliosidosis

Abstract

The Unfolded protein response (UPR),triggered by stress in the endoplasmic reticulum (ER), is a key driver ofneurodegenerative diseases. GM2 gangliosidosis, which includes Tay-Sachs andSandhoff disease, is caused by an accumulation of GM2 mainly in the brain thatleads to progressive neurodegeneration. Previously, we demonstrated in acellular model of GM2 gangliosidosis that PERK, a UPR sensor, contributes toneuronal death. There is currently no approved treatment for these disorders.Chemical chaperones like ursodeoxycholic acid (UDCA) have been found toalleviate ER stress in cell and animal models. UDCA’s ability to move acrossthe blood- brain barrier makes it interesting as a therapeutic tool. Here, wefound that UDCA significantly diminished the neurite atrophy induced by GM2accumulation in primary neuron cultures. It also decreased the up-regulation ofpro-apoptotic CHOP, a downstream PERK-signaling component. To explore itspotential mechanisms of action, in vitro kinase assays and crosslinking experimentswere performed with different variants of recombinant protein PERK, either insolution or in reconstituted liposomes. The results suggest a directinteraction between UDCA and the cytosolic domain of PERK, which promoteskinase phosphorylation and dimerization.