BMAA-protein interactions: A possible new mechanism of toxicity

Onselen, Rianita van; Downing, Tim G.

doi:10.1016/j.toxicon.2018.01.011

Cited by 37 publications

(19 citation statements)

References 45 publications

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“…While the observation that BMAA interacts very strongly with proteins causing their misfolding has not been disputed, some groups have failed to detect incorporation of BMAA into the primary structure of proteins thus calling into question the role of the misincorporation hypothesis in explaining BMAA's observed neurotoxic effects (Beri et al, 2017;Onselen et al, 2017). Subsequently, alternative mechanisms have been investigated and BMAA has been found to strongly associate with melanin, to selectively inhibit the activity of certain enzymes and to interfere with and disrupt protein refolding in vitro by associating with proteins through electrostatic interactions strong enough to resist TCA precipitation and subsequent washing with SDS or DTT (van Onselen and Downing, 2018). In particular, the interaction of BMAA with melanin and neuromelanin, which seem to have an important role in neurotoxin sequestration and neurodegeneration, as well as its ability to inhibit human catalase, an enzyme directly involved in the detoxification of β-amyloid-linked cellular toxicity, have recently been proposed to also contribute to BMAA's neurotoxicity (Delcourt et al, 2018;.…”

Section: Amino Acid Misincorporation Protein Folding and Neurodegenementioning

confidence: 99%

Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

Nunes-Costa

Magalhães

G-Fernandes

et al. 2020

Front. Aging Neurosci.

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Section: Amino Acid Misincorporation Protein Folding and Neurodegenementioning

confidence: 99%

Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

Nunes-Costa

Magalhães

G-Fernandes

et al. 2020

Front. Aging Neurosci.

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“…This work highlights the capacity of AlaRS to use its pre-transfer editing function to clear away misactivated AZE (Figure 3). On the contrary, misactivation of another np aa β-N-methylamino-L-alanine (BMAA) escapes from being edited by AlaRS 38 , because BMAA can inhibit the deacylation activity of AlaRS 38,39 , revealing an exceptional case of how a np aa can evade proofreading by an aaRS (Figure 3).…”

Section:  Editing For Non-proteinogenic Amino Acidsmentioning

confidence: 99%

The uniqueness of AlaRS and its human disease connections

2020

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Among the 20 cytoplasmic aminoacyl-tRNA synthetases (aaRSs), alanyl-tRNA synthetase (AlaRS) has unique features. AlaRS is the only aaRS that exclusively recognizes a single G3:U70 wobble base pair in the acceptor stem of tRNA, which serves as the identity element for both the synthetic and the proofreading activities of the synthetase. The recognition is relaxed during evolution and eukaryotic AlaRS can mis-aminoacylate noncognate tRNAs with a G4:U69 base pair seemingly as a deliberate gain of function for unknown reasons. Unlike other class II aaRSs, dimerization of AlaRS is not necessarily required for aminoacylation possibly due to functional compensations from the C-terminal domain (C-Ala). In contrast to other 19 cytoplasmic aaRSs that append additional domains or motifs to acquire new functions during evolution, the functional expansion of AlaRS is likely achieved through transformations of the existing C-Ala. Given both essential canonical and diverse non-canonical roles of AlaRS, dysfunction of AlaRS leads to neurodegenerative disorders in human and various pathological phenotypes in mouse models. In this review, the uniqueness of AlaRS in both physiological and pathological events is systematically discussed, with a particular focus on its novel functions gained in evolution.

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“…To account for at least some of the vast host of injuries that are possible to the highly articulated biosemiotic processes of the body, the increased presence of certain toxins, among them Monsanto's glyphosate (RoundUp) along with other environmental toxins are increasingly being scrutinized. At the level of proteinogenesis, some researchers have argued that non-coding amino acids such as beta-methylamino-L-alanine (BMAA, similar to serine; [240]- [244], canavanine (similar to arginine; [240], [241], [245], and glypohosate (similar to glycine; [145], [246], [247] can lead to erroneous interpretations and are, in some instances, misincorporated into necessary proteins [148], [248] resulting in deformed strings that lead to disease conditions including systemic autoimmunities [245], [249]- [252]. However, the relevant research, at least in the case of BMAA shows that wholesale misincorporation of non-protoeinogenic amino acids is not easily achieved in living cells [253], [254].…”

Section: Approaching and Penetrating The Nuclear Envelopementioning

confidence: 99%

From Superficial Damage to Invasion of the Nucleosome: Ranking of Morbidities by the Biosemiotic Depth Hypothesis

Oller¹,

Shaw²

2019

ijSciences

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At their most abstract level, according to a certain generalized paradigm in biosemiotic philosophy grounded in well-established mathematical proofs, valid communications from molecules upward must be formally isomorphic to the dynamic true narrative representations (TNRs) of natural language systems that vest those meaningful signs with their functional (pragmatic) content. TNRs, in DNA, RNA, proteins, and higher constructions, therefore, are requisite to health in the individual, in interactions with the larger environment, and with other organisms. In homo sapiens, the generalized biosemiotic paradigm proves that morbidities in general must always, in some manner, involve degradation of internal and external communications through TNRs in DNA, RNA, protein language, organelles, cells, tissues, and organ systems. The mathematically grounded paradigm shows that any given TNR can be superveniently degenerated, by very coarse or very fine degrees, to many distinct fictions, errors, lies, and nonsense strings out to the absolute limit of a complete erasure. The depth hypothesis asserts that if the timing and breadth of any degenerative disruption can be held equal, in fact or in principle, the depth of penetration of any disruptive factor into biosignaling representations must in theory be pathognomonic of severity in the supervened morbidities. From meiosis through conception to maturity, ceteris paribus, corruptions deeper in the developmental hierarchy must be more harmful in the morbidities they supervene. The depth hypothesis suggests a differentiation of autoimmune disorders as deeper than allergies, but less so than prion diseases, tumorigenesis, and metastatic cancers in that order. It suggests, therefore, a potentially useful generalized ranking of morbidities.

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BMAA-protein interactions: A possible new mechanism of toxicity

Cited by 37 publications

References 45 publications

Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

The uniqueness of AlaRS and its human disease connections

From Superficial Damage to Invasion of the Nucleosome: Ranking of Morbidities by the Biosemiotic Depth Hypothesis

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