Environmental Neurotoxin β-N-Methylamino-L-alanine (BMAA) as a Widely Occurring Putative Pathogenic Factor in Neurodegenerative Diseases

Lopičić, Srdjan; Svirčev, Zorica; Malešević, Tamara Palanački; Kopitović, Aleksandar; Ivanovska, Aleksandra; Meriluoto, Jussi

doi:10.3390/microorganisms10122418

Cited by 11 publications

(5 citation statements)

References 160 publications

(244 reference statements)

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“…BMAA can facilitate most of the mechanisms related to neurodegeneration [231]. Thus, Lobner and co-authors [232] demonstrated that BMAA at the concentration range of 10-100 µmol potentiates neurotoxicity induced by amyloid-β and NMDA.…”

Section: Cyanotoxins and Infectionsmentioning

confidence: 98%

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

Nugumanova¹,

Ponomarev²,

Askarova³

et al. 2023

Preprint

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Section: Cyanotoxins and Infectionsmentioning

confidence: 98%

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

Nugumanova¹,

Ponomarev²,

Askarova³

et al. 2023

Preprint

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“…Contaminated irrigation water has led to BMAA accumulation in crops without any obvious morphological alterations, making contamination hard to detect ( Mohamed et al, 2024 ). It also has the potential to biomagnify further through the trophic levels and has been found in many fish species and in seafood sold in Swedish supermarkets ( Jiang et al, 2014 ; Lopicic et al, 2022 ). Consumption of water and or fish from often algal bloom contaminated Lake Mascoma in New Hampshire has been suggested to play a large role in its almost 25 times higher annual incidence of ALS compared to the rest of the USA ( Caller et al, 2009 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Min,

Sarlus,

Harris

2024

Front. Mol. Neurosci.

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The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.

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“…Despite some contradictory research [ 56 ], an increasing body of experimental proof provides confirmation that BMAA plays a significant role in neurodegenerative diseases (ND) [ 57 , 58 , 59 ]. Some analytical methods related to liquid chromatography and fluorescence-based detection of BMAA, especially in older literature, may be prone to overestimation of BMAA concentration in studied samples and should be treated cautiously [ 60 , 61 ]. BMAA has been shown to contribute to protein misfolding, enzyme inhibition, and neuroinflammation [ 62 ].…”

Section: Cyanobacterial Toxinsmentioning

confidence: 99%

“…BMAA can facilitate most of the mechanisms related to neurodegeneration [ 61 ]. Thus, Lobner and co-authors [ 266 ] demonstrated that BMAA at the 10–100 µmol potentiates neurotoxicity induced by β-amyloid and NMDA.…”

Section: Toxin Exposure Pathwaysmentioning

confidence: 99%

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

Nugumanova

Ponomarev

Askarova

et al. 2023

Toxins

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Cyanobacteria produce a wide range of structurally diverse cyanotoxins and bioactive cyanopeptides in freshwater, marine, and terrestrial ecosystems. The health significance of these metabolites, which include genotoxic- and neurotoxic agents, is confirmed by continued associations between the occurrence of animal and human acute toxic events and, in the long term, by associations between cyanobacteria and neurodegenerative diseases. Major mechanisms related to the neurotoxicity of cyanobacteria compounds include (1) blocking of key proteins and channels; (2) inhibition of essential enzymes in mammalian cells such as protein phosphatases and phosphoprotein phosphatases as well as new molecular targets such as toll-like receptors 4 and 8. One of the widely discussed implicated mechanisms includes a misincorporation of cyanobacterial non-proteogenic amino acids. Recent research provides evidence that non-proteinogenic amino acid BMAA produced by cyanobacteria have multiple effects on translation process and bypasses the proof-reading ability of the aminoacyl-tRNA-synthetase. Aberrant proteins generated by non-canonical translation may be a factor in neuronal death and neurodegeneration. We hypothesize that the production of cyanopeptides and non-canonical amino acids is a more general mechanism, leading to mistranslation, affecting protein homeostasis, and targeting mitochondria in eukaryotic cells. It can be evolutionarily ancient and initially developed to control phytoplankton communities during algal blooms. Outcompeting gut symbiotic microorganisms may lead to dysbiosis, increased gut permeability, a shift in blood-brain-barrier functionality, and eventually, mitochondrial dysfunction in high-energy demanding neurons. A better understanding of the interaction between cyanopeptides metabolism and the nervous system will be crucial to target or to prevent neurodegenerative diseases.

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Environmental Neurotoxin β-N-Methylamino-L-alanine (BMAA) as a Widely Occurring Putative Pathogenic Factor in Neurodegenerative Diseases

Cited by 11 publications

References 160 publications

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Freshwater Cyanobacterial Toxins, Cyanopeptides and Neurodegenerative Diseases

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