β-Methylamino-L-alanine-induced protein aggregation in vitro and protection by L-serine

Quinn, Adam W; Phillips, Connor R; Violi, Jake P.; Steele, Joel R.; Johnson, Michael; Westerhausen, Mika T.; Rodgers, Kenneth J.

doi:10.1007/s00726-021-03049-w

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…This last result strongly supports a L-BMAA toxicity mediated by misincorporation during protein synthesis, probably inducing protein misfolding. Consistent with this result, both in cells ( 66 , 67 ) and in mice ( 27 ) protein misfolding appears to be the main L-BMAA toxin effect that, at least in cells, may be counteract by L-serine addiction. Notably, L-serine has been proposed as a potential therapeutic option for ALS ( 68 ) and some phase 2 clinical trials (ClinicalTrials.gov Identifier: NCT03580616 for ALS and NCT03062449 for AD) are ongoing.…”

Section: Discussionsupporting

confidence: 67%

“…In fact, two marker of autophagy impairment (LC3B and p62), analyzed by western blot, are upregulated by the treatment ( Figure 2 ). In agreement, in NSC-34 cells boosting autophagy rescues the L-BMAA-induced toxicity ( 74 ) although a different research suggests that L-BMAA stimulates the chaperone-mediated autophagy activity evaluated by the increase in Lamp2a receptor staining upon L-BMAA treatment ( 67 ).…”

Section: Discussionmentioning

confidence: 73%

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Evaluation of cyanotoxin L-BMAA effect on α-synuclein and TDP43 proteinopathy

Sini,

Galleri,

Ciampelli

et al. 2024

Front. Immunol.

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The complex interplay between genetic and environmental factors is considered the cause of neurodegenerative diseases including Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Among the environmental factors, toxins produced by cyanobacteria have received much attention due to the significant increase in cyanobacteria growth worldwide. In particular, L-BMAA toxin, produced by diverse taxa of cyanobacteria, dinoflagellates and diatoms, has been extensively correlated to neurodegeneration. The molecular mechanism of L-BMAA neurotoxicity is still cryptic and far from being understood. In this research article, we have investigated the molecular pathways altered by L-BMAA exposure in cell systems, highlighting a significant increase in specific stress pathways and an impairment in autophagic processes. Interestingly, these changes lead to the accumulation of both α-synuclein and TDP43, which are correlated with PD and ALS proteinopathy, respectively. Finally, we were able to demonstrate specific alterations of TDP43 WT or pathological mutants with respect to protein accumulation, aggregation and cytoplasmic translocation, some of the typical features of both sporadic and familial ALS.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 73%

Evaluation of cyanotoxin L-BMAA effect on α-synuclein and TDP43 proteinopathy

Sini,

Galleri,

Ciampelli

et al. 2024

Front. Immunol.

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“…Supplementation with L-serine would be of interest in those cases of ALS where there is suspicion of environmental contamination by cyanobacteria [49,51,52,53]. In addition, as we said above, the amount of L-serine and ROS regulates the plastic metabolic response by p53 in muscle [36,37].…”

Section: L-serine Amino Acidmentioning

confidence: 97%

“…This pathway represents the only way to synthesize serine in most organisms, except in plants. Taken together, these convergent lines of evidence indicate that the p53 pathway controls a highly branched metabolic network that is essential for maintaining cellular homeostasis and cannot be ignored in diseases such as ALS [36,37].…”

Section: Als Is An Immunometabolic Disease That Commences With P53-modulated Skeletal Muscle Energy Impairmentmentioning

confidence: 99%

P53 Protein Modulates Muscle Metabolism and Generates a Non-Genetic Risk Environment that Contributes to Triggering Amyotrophic Lateral Sclerosis

Espina-Zambrano¹

2022

Preprint

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Amyotrophic lateral sclerosis (ALS) is also called "motor neuron disease”. In this review, we propose that ALS is not just a neuromotor disorder, but begins as a disorder of P53-modulated skeletal muscle metabolism, leading to failures at the energy state of the cells, incorrect redox states, motor denervation, and a loss of muscle fibers. Motoneurons die as a consequence of the lack of muscular feedback, and the oligomeric TDP43 aggregates progressively and relentlessly lead to mistakes in peripheral immune self-tolerance sustained over time. An effective treatment has not been found for this devastating pathology, as for 152 years the target has not been accurately defined. Scientists and doctors should consider new knowledge regarding ALS and consider immunomodulatory therapies that, based on genetic analysis and symptoms, can be combined with compounds that regulate metabolism and promote the elimination of useless organelles and cells. What if ALS could be cured as a result of seeing motor neuron disease differently? This review aims to develop that goal and change the paradigm of our understanding of ALS.

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“…We previously proposed, based on in vitro studies, that BMAA was capable of exchanging for L-serine in protein synthesis [31]. It was subsequently shown that L-serine reduced BMAA-induced ER stress [32][33][34] and decreased the levels of ubiquitin-positive aggregates in cells suggesting that L-serine was capable of reducing the toxicity of BMAA [35]. When examined in vivo, co-administration of L-serine with BMAA also had a significant impact on the neuropathological changes reported in the vervet studies significantly reducing the density of NFT [29], the amount of reactive gliosis, and the number of protein inclusions in motor neurons [29,30].…”

Section: Introductionmentioning

confidence: 99%

Effects of the Toxic Non-Protein Amino Acid β-Methylamino-L-Alanine (BMAA) on Intracellular Amino Acid Levels in Neuroblastoma Cells

Violi,

Pu,

Pravadali-Cekic

et al. 2023

Toxins

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The cyanobacterial non-protein amino acid (AA) β-Methylamino-L-alanine (BMAA) is considered to be a neurotoxin. BMAA caused histopathological changes in brains and spinal cords of primates consistent with some of those seen in early motor neuron disease; however, supplementation with L-serine protected against some of those changes. We examined the impact of BMAA on AA concentrations in human neuroblastoma cells in vitro. Cells were treated with 1000 µM BMAA and intracellular free AA concentrations in treated and control cells were compared at six time-points over a 48 h culture period. BMAA had a profound effect on intracellular AA levels at specific time points but in most cases, AA homeostasis was re-established in the cell. The most heavily impacted amino acid was serine which was depleted in BMAA-treated cells from 9 h onwards. Correction of serine depletion could be a factor in the observation that supplementation with L-serine protects against BMAA toxicity in vitro and in vivo. AAs that could potentially be involved in protection against BMAA-induced oxidation such as histidine, tyrosine, and phenylalanine were depleted in cells at later time points.

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β-Methylamino-L-alanine-induced protein aggregation in vitro and protection by L-serine

Cited by 8 publications

References 47 publications

Evaluation of cyanotoxin L-BMAA effect on α-synuclein and TDP43 proteinopathy

Evaluation of cyanotoxin L-BMAA effect on α-synuclein and TDP43 proteinopathy

P53 Protein Modulates Muscle Metabolism and Generates a Non-Genetic Risk Environment that Contributes to Triggering Amyotrophic Lateral Sclerosis

Effects of the Toxic Non-Protein Amino Acid β-Methylamino-L-Alanine (BMAA) on Intracellular Amino Acid Levels in Neuroblastoma Cells

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