β-N-Methylamino-L-alanine (BMAA) perturbs alanine, aspartate and glutamate metabolism pathways in human neuroblastoma cells as determined by metabolic profiling.
β-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid that induces long-term cognitive deficits, as well as an increased neurodegeneration and intracellular fibril formation in the hippocampus of adult rodents following short-time neonatal exposure and in vervet monkey brain following long-term exposure. It has also been proposed to be involved in the etiology of neurodegenerative disease in humans. The aim of this study was to identify metabolic effects not related to excitotoxicity or oxidative stress in human neuroblastoma SH-SY5Y cells. The effects of BMAA (50, 250, 1000 µM) for 24 h on cells differentiated with retinoic acid were studied. Samples were analyzed using LC-MS and NMR spectroscopy to detect altered intracellular polar metabolites. The analysis performed, followed by multivariate pattern recognition techniques, revealed significant perturbations in protein biosynthesis, amino acid metabolism pathways and citrate cycle. Of specific interest were the BMAA-induced alterations in alanine, aspartate and glutamate metabolism and as well as alterations in various neurotransmitters/neuromodulators such as GABA and taurine. The results indicate that BMAA can interfere with metabolic pathways involved in neurotransmission in human neuroblastoma cells.
Division of Analytical Pharmaceutical Chemistry, Uppsala University, Box 574, 751 23, Uppsala, Sweden. mikael.engskog@farmkemi.uu.se.
Mikael K R
MK
Engskog
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 23, Uppsala, Sweden.
Lisa
L
Ersson
Division of Analytical Pharmaceutical Chemistry, Uppsala University, Box 574, 751 23, Uppsala, Sweden.
Jakob
J
Haglöf
Division of Analytical Pharmaceutical Chemistry, Uppsala University, Box 574, 751 23, Uppsala, Sweden.|Medical Product Agency, Box 26, Dag Hammarskjölds väg 42, 751 03, Uppsala, Sweden.
Torbjörn
T
Arvidsson
Division of Analytical Pharmaceutical Chemistry, Uppsala University, Box 574, 751 23, Uppsala, Sweden.
Curt
C
Pettersson
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 23, Uppsala, Sweden.
Eva
E
Brittebo
D000409:Alanine / Q000378:metabolism*; D000599:Amino Acids, Diamino / Q000633:toxicity*; D001224:Aspartic Acid / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000087522:Cyanobacteria Toxins; D003603:Cytotoxins / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D025341:Principal Component Analysis; D013654:Taurine / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D003603:Cytotoxins; C001824:beta-N-methylamino-L-alanine; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D014212:Tretinoin; D000409:Alanine
BMAA; Global metabolite profiling; MS; Metabolism; NMR; Neurotoxin