Date Published: March 8, 2012
Publisher: Public Library of Science
Author(s): Jianmin Chen, Karl Herrup, Hyoung-gon Lee. http://doi.org/10.1371/journal.pone.0033177
Glutamine is the most abundant free amino acid in the human blood stream and is ‘conditionally essential’ to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H2O2, zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer’s disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD.
Glutamine is the most abundant free amino acid in the human blood stream. It is typically classified as a ‘non-essential’ amino acid because it can be made from TCA metabolites by most cells. A more accurate classification of the body’s need for glutamine, however, would be the term ‘conditionally essential’. Many cell types are unable to survive in the complete absence of glutamine. Indeed, in certain B-cell lines supranormal concentrations are required. The value of glutamine is particularly apparent during stress. It becomes essential in organs or organ systems weakened by sickness, surgery or injury. Glutamine can regulate a variety of target genes involved in cell proliferation, differentiation and survival. It accomplishes this by altering the behavior of a range of transcription factors, including NFκB, through which the anti-inflammatory role of glutamine may be mediated . A molecular explanation for the broad cellular dependence on glutamine remains elusive, but a key insight has emerged from recent studies showing that high intracellular glutamine is rate limiting for the uptake of several essential amino acids through the SLC7A5/SLC3A2 bidirectional transporter .
Our data provide strong support for a neuroprotective effect of glutamine supplementation in a variety of different situations. The molecular nature of this protection is complex and reflects the levels intra- and extra-cellular glutamine as well as the levels and state of oxidation of the synthetic enzyme, glutamine synthetase (GS).