Mechanisms of l-Serine Neuroprotection in vitro Include ER Proteostasis Regulation

β-N-methylamino-l-alanine (L-BMAA) is a neurotoxic non-protein amino acid produced by cyanobacteria. Recently, chronic dietary exposure to l-BMAA was shown to trigger neuropathology in nonhuman primates consistent with Guamanian ALS/PDC, a paralytic disease that afflicts Chamorro villagers who consume traditional food items contaminated with l-BMAA. However, the addition of the naturally occurring amino acid l-serine to the diet of the nonhuman primates resulted in a significant reduction in ALS/PDC neuropathology. l-serine is a dietary amino acid that plays a crucial role in central nervous system development, neuronal signaling, and synaptic plasticity and has been shown to impart neuroprotection from l-BMAA-induced neurotoxicity both in vitro and in vivo. We have previously shown that l-serine prevents the formation of autofluorescent aggregates and death by apoptosis in human cell lines and primary cells. These effects are likely imparted by l-serine blocking incorporation of l-BMAA into proteins hence preventing proteotoxic stress. However, there are likely other mechanisms for l-serine-mediated neuroprotection. Here, we explore the molecular mechanisms of l-serine neuroprotection using a human unfolded protein response real-time PCR array with genes from the ER stress and UPR pathways, and western blotting. We report that l-serine caused the differential expression of many of the same genes as l-BMAA, even though concentrations of l-serine in the culture medium were ten times lower than that of l-BMAA. We propose that l-serine may be functioning as a small proteostasis regulator, in effect altering the cells to quickly respond to a possible oxidative insult, thus favoring a return to homeostasis.