Aberrant Reduction of Short-Chain Fatty Acid (SCFA) Receptor GPR41 and Transporter MCT4 in Prion-Infected Rodent and Cell Models

Mounting evidence shows that short-chain fatty acids (SCFAs), derived mainly from intestinal bacteria, play a significant role in maintaining the homeostasis of the immune system and the central nervous system (CNS). SCFAs, directly or indirectly mediated by SCFA receptors and transporters in neuronal cells, participate in the pathophysiological processes of various neurodegenerative diseases, but their roles in prion diseases are rarely addressed. Here, the abnormal changes in SCFA receptors and transporters in a prion-infected cell line and in the brains of several prion-scrapie-infected rodent models were evaluated by various methods. Markedly decreased GPR41 and MCT4 levels were observed in the brains of scrapie-infected rodents at the terminal stage and in the prion-infected cell line, whereas GPR43 and MCT1 levels did not change significantly. Morphological assays identified close colocalization of both GPR41 and MCT4 with NeuN-positive cells, while only a low amount was observed with Iba1-positive and GFAP-positive cells in the brains of prion-infected mice. Reduction of HO-1, an antioxidative agent in Nrf2 signaling, was observed in the brains of both prion-infected rodent models and the prion-infected cell line. Reductions of GPR41 and MCT4 in the prion-infected cell line were reversible after the removal of prion replication and stimulation with SCFA (sodium propionate) or a GPR41 agonist, accompanied by recovering the HO-1 level and improving cell viability. Our data presented here demonstrate a correlation between alterations in GPR41/MCT4 expression and the shifts in cellular composition that accompany prion pathogenesis. Furthermore, we explore the potential association between SCFA signaling and prion neurotoxicity, identifying it as a crucial area for future research endeavors.