Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice

Arnold, Frederick; Burns, Maureen; Chiu, Yu-Chun; Carvalho, Joana; Nguyen, Annee; Ralph, P.C; Spada, Albert R. La; Bennett, Craig L.

doi:10.1016/j.neurobiolaging.2023.02.010

Cited by 10 publications

(8 citation statements)

References 63 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: 69%

“…demonstrated that chronic exposure to L-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and an ALS phenotype ( 26 ) while Arnold et al. showed low dose of L-BMAA associated to a low expression of ALS TDP-43 Q331K mutant results in a motor phenotype that is absent from either lesion alone ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…L-BMAA was found, in postmortem brain tissues from ALS and PD’s patients ( 20 – 22 ); induced motor-system diseases in monkeys ( 23 – 25 ),; cell death and astrogliosis in mice, accompanied by TDP-43 cytoplasmic accumulation ( 26 ). Chronic low-dose BMAA exposure, combined with low expression of ALS TDP-43 mutation (Q331K) expression, resulted in motor phenotype potentially involving the unfolded protein response (UPR) pathway ( 27 ). Finally, L-BMAA toxicity was confirmed in various cellular models ( 3 , 28 ), though the molecular mechanisms varied among cell types ( 29 ).…”

Section: Introductionmentioning

confidence: 99%

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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: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…While these results suggest a possible mechanism for increased synaptic glutamate and excitotoxicity, we must also acknowledge that only 10–20% of patients with FALS harbor SOD1 mutations [ 85 ], and SOD1 ALS represents a major outlier in that the hallmark ALS pathology of TDP-43 aggregates are absent in this form of disease [ 1 ]. Hence, these hypotheses should be tested in other models of FALS, as well as models of SALS (once available) [ 86 ], to provide a more complete mechanistic understanding.…”

Section: Primary Excitotoxic Processesmentioning

confidence: 99%

Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration

Arnold,

Putka,

Raychaudhuri

et al. 2024

IJMS

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Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. ‘Primary pathways’ include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons—all of which have been observed in ALS patients and model systems. ‘Secondary pathways’ include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.

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“…Epidemiological work has shown a significant association between exposure to cycad and neurological disease on Guam [ 11 ]. Cycad seeds are known to contain several potentially toxic agents, e.g., cycasin and its aglycone methylazoxymethanol (MAM) [ 12 , 13 ] and β-N-methylamino-L-alanine (BMAA) [ 14 , 15 ], which have both been tenuously linked to neurological disease in Guam. The cycad-associated toxin MAM is a potent DNA alkylating agent that has been shown to induce O 6 -methylguanine (O 6 -mG) lesions in DNA [ 13 ].…”

mentioning

confidence: 99%

The cycad genotoxin methylazoxymethanol, linked to Guam ALS/PDC, induces transcriptional mutagenesis

Verheijen,

Chung,

Thompson

et al. 2024

acta neuropathol commun

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Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice

Cited by 10 publications

References 63 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

Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration

The cycad genotoxin methylazoxymethanol, linked to Guam ALS/PDC, induces transcriptional mutagenesis

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