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Okle, O.* ; Stemmer, K. ; Deschl, U.* ; Dietrich, D.R.*

L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations.

Toxicol. Sci. 131, 217-224 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
The cyanobacterial L-BMAA (β-N-methylamino-L-alanine) is described as a low potency excitotoxin, possibly a factor in the increased incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism dementia complex (PDC) on Guam. The latter association is intensively disputed, as L-BMAA concentrations required for toxic effects exceed those assumed to occur via food. The question thus was raised whether L-BMAA leads to neurodegeneration at non-excitotoxic conditions. Using human SH-SY5Y neuroblastoma cells, L-BMAA-transport, incorporation into proteins and subsequent impairment of cellular protein homeostasis were investigated. Binding of L-BMAA to intracellular proteins, but no clear protein incorporation was detected in response to (14)C-L-BMAA exposures. Nevertheless, low L-BMAA concentrations (≥0.1 mM, 48 hours) increased protein ubiquitination, 20S proteasomal and caspase 12 activity, expression of the ER-stress marker CHOP, and enhanced phosphorylation of elf2α in SH-SY5Y. In contrast, high L-BMAA concentrations (≥1 mM, 48 hours) increased ROS and protein oxidization, which were partially ameliorated by co-incubation vitamin E. L-BMAA mediated cytotoxicity was observable 48 hours following ≥2 mM L-BMAA treatment. Consequently, the data presented here suggest that low L-BMAA concentrations result in a dysregulation of the cellular protein homeostasis with ensuing ER stress that is independent from high concentration effects such as excitotoxicity and oxidative stress. Thus, the latter could be a contributing factor in the onset and slow progression of ALS/PDC on Guam.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords L-BMAA; neurotoxin; unfolded protein response (UPR); ALS/PDC; ER stress; ER associated degradation (ERAD); Methylamino-l-alanine ; Amyotrophic-lateral-sclerosis ; Blood-brain-barrier ; 2-amino-3-(methylamino)-propanoic Acid Bmaa ; Endoplasmic-reticulum Stress ; Neurodegenerative Disease ; Cyanobacterial Neurotoxins ; Parkinsonism-dementia ; Chamorro People ; Flying Foxes
ISSN (print) / ISBN 1096-6080
e-ISSN 1096-0929
Journal Toxicological Sciences
Quellenangaben Volume: 131, Issue: 1, Pages: 217-224 Article Number: , Supplement: ,
Publisher Oxford University Press
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)