Parkinson-dementia complex and development of a new stable isotope dilution assay for BMAA detection in tissue.
Beta-methylamino-L-alanine (BMAA) has been proposed as a global contributor to neurodegenerative diseases, including Parkinson-dementia complex (PDC) of Guam and Alzheimer's disease (AD). The literature on the effects of BMAA is conflicting with some but not all in vitro data supporting a neurotoxic action, and experimental animal data failing to replicate the pattern of neurodegeneration of these human diseases, even at very high exposures. Recently, BMAA has been reported in human brain from individuals afflicted with PDC or AD. Some of the BMAA in human tissue reportedly is freely extractable (free) while some is protein-associated and liberated by techniques that hydrolyze the peptide bond. The latter is especially intriguing since BMAA is a non-proteinogenic amino acid that has no known tRNA. We attempted to replicate these findings with techniques similar to those used by others; despite more than adequate sensitivity, we were unable to detect free BMAA. Recently, using a novel stable isotope dilution assay, we again were unable to detect free or protein-associated BMAA in human cerebrum. Here we review the development of our new assay for tissue detection of BMAA and show that we are able to detect free BMAA in liver but not cerebrum, nor do we detect any protein-associated BMAA in mice fed this amino acid. These studies demonstrate the importance of a sensitive and specific assay for tissue BMAA and seriously challenge the proposal that BMAA is accumulating in human brain.
Snyder
Laura R
LR
Department of Chemistry, University of Washington, Seattle, WA, USA.
Cruz-Aguado
Reyniel
R
Sadilek
Martin
M
Galasko
Douglas
D
Shaw
Christopher A
CA
Montine
Thomas J
TJ
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000599:Amino Acids, Diamino / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002138:Calibration; D016022:Case-Control Studies; D054022:Cerebrum / Q000378:metabolism*; D000087522:Cyanobacteria Toxins; D003704:Dementia / Q000208:ethnology / Q000209:etiology / Q000378:metabolism*; D003903:Deuterium; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006141:Guam / Q000453:epidemiology; D006801:Humans; D007201:Indicator Dilution Techniques / Q000592:standards; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008875:Middle Aged; D010300:Parkinson Disease / Q000208:ethnology / Q000209:etiology / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014861:Washington / Q000453:epidemiology
D000599:Amino Acids, Diamino; D015415:Biomarkers; D000087522:Cyanobacteria Toxins; C001824:beta-N-methylamino-L-alanine; D003903:Deuterium