β-N-methylamino-l-alanine causes neurological and pathological phenotypes mimicking Amyotrophic Lateral Sclerosis (ALS): The first step towards an experimental model for sporadic ALS

Munck, Estefanía de; Muñoz-Sáez, Emma; Miguel, B.G.; Solas, M.T.; Ojeda, Irene; Martı́nez, Ana; Gil, Carmen; Arahuetes, R.M.

doi:10.1016/j.etap.2013.04.007

Cited by 64 publications

(59 citation statements)

References 62 publications

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“…Moreover, it correlates with the volume loss in the motor cortex detected. These findings are consistent with the detection of damaged mitochondria in nervous tissue of rats treated with l-BMAA (de Munck et al, 2013), suggesting that excitotoxic mechanisms might play a role in the pathogenesis developed due to the action of this neurotoxic.…”

Section: Impaired Neurotransmiters Systemssupporting

confidence: 92%

“…The muscle atrophy is consistent with results obtained in previous studies with rats treated with this dose of l-BMAA (de Munck et al, 2013), which describes a loss of motor control, analyzed by functional tests, which may be due to alterations in several points of the motor pathway.…”

Section: Morphometric Changes In Mri Studysupporting

confidence: 92%

“…Recently, we have proposed in our research group a model of ALS in rats by administration of l-BMAA (de Munck et al, 2013), which mimics many of the pathophysiological features of ALS in humans. In the present work we delve into the characterization of this model focusing on the possible morphometric changes detected by Magnetic Resonance Imaging (MRI) and neurotransmitter levels in animals treated with l-BMAA.…”

Section: Als Animal Modelsmentioning

confidence: 98%

“…In order to assess long term evolution of symptoms in treated animals, the neurological tests were carried out, with 10 control and 10 treated animals, as described by de Munck et al (2013), once a week during 14 months. Briefly, the neurological assess was carried out with three diferent tests: ambulation, tail suspension test and strength test.…”

Section: Neurological Evaluationmentioning

confidence: 99%

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Morphometric and neurochemical alterations found in l-BMAA treated rats

Munck

Muñoz-Sáez

Miguel

et al. 2015

Environmental Toxicology and Pharmacology

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis that reflects the motoneurons' degeneration. Several studies support the relationship between β-N-methylamino-l-alanine (l-BMAA), a neurotoxic amino acid produced by cyanobacteria and diatoms, and the sporadic occurrence of ALS and other neurodegenerative diseases. Therefore, the study of its neurotoxicity mechanisms has assumed great relevance in recent years. Recently, our research team has proposed a sporadic ALS animal model by l-BMAA administration in rats, which displays many pathophysiological features of human ALS. In this paper, we deepen the characterization of this model corroborating the occurrence of alterations present in ALS patients such as decreased muscle volume, thinning of the motor cortex, enlarged brain's lateral ventricles, and alteration of both bulbar nuclei and neurotransmitters' levels. Therefore, we conclude that l-BMAA treated rats could be a good model which mimics degenerative features that ALS causes in humans.

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Section: Impaired Neurotransmiters Systemssupporting

confidence: 92%

Section: Morphometric Changes In Mri Studysupporting

confidence: 92%

Section: Als Animal Modelsmentioning

confidence: 98%

Section: Neurological Evaluationmentioning

confidence: 99%

See 2 more Smart Citations

Morphometric and neurochemical alterations found in l-BMAA treated rats

Munck

Muñoz-Sáez

Miguel

et al. 2015

Environmental Toxicology and Pharmacology

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“…The nonprotein amino acid β-Nmethylamino-L-alanine (BMAA) has been implicated as a potential environmental factor in PD, ALS, AD, and other neurodegenerative disorders (9)(10)(11). Although the neurotoxic effects of BMAA are not conclusive, BMAA concentrations as low as 30 μM can cause selective death of motor neurons (12), and a 10-μM concentration can potentiate neuronal injury induced by exposure to amyloid-β, 1-methyl-4-phenylpyridinium, or methylmercury in mixed cortical cultures (13).…”

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confidence: 99%

Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam

Arif

Kazim

Grundke‐Iqbal

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Parkinsonism-dementia (PD) of Guam is a neurodegenerative disease with parkinsonism and early-onset Alzheimer-like dementia associated with neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein, tau. β-N-methylamino-Lalanine (BMAA) has been suspected of being involved in the etiology of PD, but the mechanism by which BMAA leads to tau hyperphosphorylation is not known. We found a decrease in protein phosphatase 2A (PP2A) activity associated with an increase in inhibitory phosphorylation of its catalytic subunit PP2Ac at Tyr 307 and abnormal hyperphosphorylation of tau in brains of patients who had Guam PD. To test the possible involvement of BMAA in the etiopathogenesis of PD, we studied the effect of this environmental neurotoxin on PP2A activity and tau hyperphosphorylation in mouse primary neuronal cultures and metabolically active rat brain slices. BMAA treatment significantly decreased PP2A activity, with a concomitant increase in tau kinase activity resulting in elevated tau hyperphosphorylation at PP2A favorable sites. Moreover, we found an increase in the phosphorylation of PP2Ac at Tyr 307 in BMAA-treated rat brains. Pretreatment with metabotropic glutamate receptor 5 (mGluR5) and Src antagonists blocked the BMAAinduced inhibition of PP2A and the abnormal hyperphosphorylation of tau, indicating the involvement of an Src-dependent PP2A pathway. Coimmunoprecipitation experiments showed that BMAA treatment dissociated PP2Ac from mGluR5, making it available for phosphorylation at Tyr 307 . These findings suggest a scenario in which BMAA can lead to tau pathology by inhibiting PP2A through the activation of mGluR5, the consequent release of PP2Ac from the mGluR5-PP2A complex, and its phosphorylation at Tyr 307 by Src.Alzheimer's disease | amyotrophic lateral sclerosis | tauopathies | tau phosphorylation | cycad

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2017

Neural Dynamics of Neurological Disease

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β-N-methylamino-l-alanine causes neurological and pathological phenotypes mimicking Amyotrophic Lateral Sclerosis (ALS): The first step towards an experimental model for sporadic ALS

Cited by 64 publications

References 62 publications

Morphometric and neurochemical alterations found in l-BMAA treated rats

Morphometric and neurochemical alterations found in l-BMAA treated rats

Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam

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