In vivo and In vitro investigations to elucidate the associations of B-N-methylamino-L-alanine with proteins
- Authors: Van Onselen, Rianita
- Date: 2015
- Subjects: Cyanobacteria , Bioaccumulation
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/4923 , vital:20767
- Description: The cyanobacterially synthesized non-canonical amino acid β-N-methylamino-ʟ-alanine (BMAA) has been proposed to be a causative agent in the development of sporadic neurodegenerative diseases. This neurotoxin bioaccumulates and biomagnifies with increasing trophic levels in ecosystems by associating with proteins. It has been suggested that these associations with host proteins also serve as a reservoir from where BMAA is slowly released with normal protein catabolism, resulting in a continuous low level exposure. However, the nature of these associations remains poorly defined. The widely accepted hypothesis regarding the nature of these associations is that BMAA associates with proteins through primary incorporation into proteins with specific replacement of serine. In addition to excitotoxicity, BMAA misincorporation has been proposed as a potential mechanism of toxicity because of its link to protein tangle diseases. Interactions between BMAA and proteins that are not the result of misincorporation, have also been observed. However, the nature of these non-primary associations has not been investigated. This study focussed on establishing whether BMAA is misincorporated into host proteins with consequent toxicity, and on elucidating the nature of the BMAA-protein associations not linked to primary incorporation. In comparative studies between BMAA and canavanine, an arginine analogue known to misincorporate, exposure to BMAA did not result in any toxicity in prokaryotes or in an undifferentiated eukaryotic mammalian cell line, in contrast to what was observed upon canavanine exposure. Differentiation of the cell line with nerve growth factor to express glutamate receptors resulted in marked toxicity upon BMAA exposure, highlighting excitoxicity as the main mechanism of BMAA toxicity. Furthermore, it was demonstrated that BMAA interacts with free amino acids and proteins in the absence of de novo protein synthesis, causing enzyme inhibition and protein misfolding. It was concluded that BMAA does not interact with proteins through primary incorporation and that the observed associations are the result of an interaction between BMAA and amino acid side chains to form covalent bonds.
- Full Text:
- Date Issued: 2015
- Authors: Van Onselen, Rianita
- Date: 2015
- Subjects: Cyanobacteria , Bioaccumulation
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/4923 , vital:20767
- Description: The cyanobacterially synthesized non-canonical amino acid β-N-methylamino-ʟ-alanine (BMAA) has been proposed to be a causative agent in the development of sporadic neurodegenerative diseases. This neurotoxin bioaccumulates and biomagnifies with increasing trophic levels in ecosystems by associating with proteins. It has been suggested that these associations with host proteins also serve as a reservoir from where BMAA is slowly released with normal protein catabolism, resulting in a continuous low level exposure. However, the nature of these associations remains poorly defined. The widely accepted hypothesis regarding the nature of these associations is that BMAA associates with proteins through primary incorporation into proteins with specific replacement of serine. In addition to excitotoxicity, BMAA misincorporation has been proposed as a potential mechanism of toxicity because of its link to protein tangle diseases. Interactions between BMAA and proteins that are not the result of misincorporation, have also been observed. However, the nature of these non-primary associations has not been investigated. This study focussed on establishing whether BMAA is misincorporated into host proteins with consequent toxicity, and on elucidating the nature of the BMAA-protein associations not linked to primary incorporation. In comparative studies between BMAA and canavanine, an arginine analogue known to misincorporate, exposure to BMAA did not result in any toxicity in prokaryotes or in an undifferentiated eukaryotic mammalian cell line, in contrast to what was observed upon canavanine exposure. Differentiation of the cell line with nerve growth factor to express glutamate receptors resulted in marked toxicity upon BMAA exposure, highlighting excitoxicity as the main mechanism of BMAA toxicity. Furthermore, it was demonstrated that BMAA interacts with free amino acids and proteins in the absence of de novo protein synthesis, causing enzyme inhibition and protein misfolding. It was concluded that BMAA does not interact with proteins through primary incorporation and that the observed associations are the result of an interaction between BMAA and amino acid side chains to form covalent bonds.
- Full Text:
- Date Issued: 2015
The metabolism and environmental fate of the cyanobacterial neurotoxin Beta-N-methylamino-L-alanine
- Authors: Downing, Simoné
- Date: 2015
- Subjects: Cyanobacteria , Neurotoxic agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10948/4225 , vital:20569
- Description: The neurotoxic amino acid β-‐N-‐methylamino-Lalanine (BMAA)is present in environmentally ubiquitous cyanobacteria and bioaccumulates and biomagnifies within the environment. The implication of BMAA in the development of neurodegenerative disease has raised concerns over the potential risk of human exposure to this neurotoxin, and has focussed attention on identifying possible routes of exposure that include direct contact with cyanobacteria and the ingestion of BMAA-‐containing plant and animal products.
- Full Text:
- Date Issued: 2015
- Authors: Downing, Simoné
- Date: 2015
- Subjects: Cyanobacteria , Neurotoxic agents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: http://hdl.handle.net/10948/4225 , vital:20569
- Description: The neurotoxic amino acid β-‐N-‐methylamino-Lalanine (BMAA)is present in environmentally ubiquitous cyanobacteria and bioaccumulates and biomagnifies within the environment. The implication of BMAA in the development of neurodegenerative disease has raised concerns over the potential risk of human exposure to this neurotoxin, and has focussed attention on identifying possible routes of exposure that include direct contact with cyanobacteria and the ingestion of BMAA-‐containing plant and animal products.
- Full Text:
- Date Issued: 2015
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