Morphometric and neurochemical alterations found in l-BMAA treated rats

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

doi:10.1016/j.etap.2015.04.022

Cited by 25 publications

(14 citation statements)

References 80 publications

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“…The latter is a phenomenon associated to pathologies of Alzheimer’s disease and Parkinsonism. Also, an increase in modified and aggregated TAR DNA-binding protein 43 (TDP-43), a hallmark of ALS, has been found to associate with BMAA exposure in both neuroblastoma cells 18 and in injected and dietary exposed animals 19 20 . The changes in TDP-43 were observed together with increased levels and phosphorylation in glycogen synthase kinase 3 (GSK3) isoforms.…”

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confidence: 99%

Quantitative proteomics analysis of zebrafish exposed to sub-lethal dosages of β-methyl-amino-L-alanine (BMAA)

Frøyset

Khan

Fladmark

2016

Sci Rep

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The non-protein amino acid β-methylamino-L-alanine (BMAA) is a neurotoxin present in microalgae and shown to accumulate in the food web. BMAA has been linked to the complex neurodegenerative disorder of Guam and to increased incidents sporadic ALS. Two main neurotoxic routes are suggested; an excitotoxic by acting as an agonist towards glutamate receptors and a metabolic by misincorporating into cellular proteins. We have used zebrafish, an increasingly used model for neurodegenerative diseases, to further identify signaling components involved in BMAA-induced toxicity. Zebrafish embryos were exposed to sub-lethal dosages of BMAA and a label-free proteomics analysis was conducted on larvae 4 days post fertilization. The exposed larvae showed no developmental abnormalities, but a reduced heart rate and increased expression of GSK3 isoforms. Search towards a reviewed database containing 2968 entries identified 480 proteins. Only 17 of these were regulated 2-fold or more in the exposed larvae. Seven of these proteins could be associated to glutamate receptor signaling and recycling. The remaining nine have all been linked to disturbance in protein homeostasis, reactive oxygen species (ROS) development or neuronal cell death. We also found that BMAA influenced the endocannabinoid system by up-regulation of fatty acid amide hydrolase (FAAH) and that FAAH inhibitor URB597 reduced the BMAA effect on heart rate and GSK3 expression.

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confidence: 99%

Quantitative proteomics analysis of zebrafish exposed to sub-lethal dosages of β-methyl-amino-L-alanine (BMAA)

Frøyset

Khan

Fladmark

2016

Sci Rep

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“…Therefore, although there are many previous studies regarding L-BMAA toxicity [ 10 ], and adequate disease model for testing potential drugs has not achieved yet, and the SOD1 G93A transgenic mouse that mimic some fALS, representing minority of ALS cases, is the only ALS murine model used in drug discovery [ 11 ]. In previous work we have reported an experimental model of motor neuron disease in rats by their treatment with L-BMAA [ 12 ], [ 13 ], [ 14 ], that would allow not only for the study of the pathological neurodegenerative mechanism but also for the discovery of effective drugs that stop or delay the progression of this fatal disease.…”

Section: Introductionmentioning

confidence: 99%

“…L-BMAA treated animals present motor deficiencies together with ultrastructural alterations in both the endoplasmic reticulum and the mitochondria [ 12 , 13 , 15 ]. Molecularly, alterations of TAR DNA-binding protein 43 (TDP-43) and glycogen synthase kinase 3 (GSK-3), two major markers of neurodegenerative diseases, are found.…”

Section: Introductionmentioning

confidence: 99%

Small GSK-3 Inhibitor Shows Efficacy in a Motor Neuron Disease Murine Model Modulating Autophagy

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease that has no effective treatment up to date. Drug discovery tasks have been hampered due to the lack of knowledge in its molecular etiology together with the limited animal models for research. Recently, a motor neuron disease animal model has been developed using β-N-methylamino-L-alanine (L-BMAA), a neurotoxic amino acid related to the appearing of ALS. In the present work, the neuroprotective role of VP2.51, a small heterocyclic GSK-3 inhibitor, is analysed in this novel murine model together with the analysis of autophagy. VP2.51 daily administration for two weeks, starting the first day after L-BMAA treatment, leads to total recovery of neurological symptoms and prevents the activation of autophagic processes in rats. These results show that the L-BMAA murine model can be used to test the efficacy of new drugs. In addition, the results confirm the therapeutic potential of GSK-3 inhibitors, and specially VP2.51, for the disease-modifying future treatment of motor neuron disorders like ALS.

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“…[2][3][4][5][6][7] Notably, several studies have supported the relationship between L-BMAA and sporadic ALS. 8,9 Beyond this, the research in Guam suggests that ALS/PDC complex was also due to L-BMAA contained in the seeds of the Cycas micronesica and consumed by the Chamorro there. 10 Both Guamanian ALS and sporadic ALS could be caused by the oral, 11 sc, 12 I.V., 5 I.P.…”

Section: Introductionmentioning

confidence: 99%

Intravenous injection of l-BMAA induces a rat model with comprehensive characteristics of amyotrophic lateral sclerosis/Parkinson–dementia complex

Tian

Jiang

Wang

et al. 2015

Toxicology Research

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Non-protein amino acid beta--methylamino-l-alanine (l-BMAA) is a neurotoxin that was associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinson-Dementia Complex (ALS/PDC) in Guam. This neurotoxin has been implicated as a potential environmental factor in amyotrophic lateral sclerosis, Alzheimer's disease and other neurodegenerative diseases, and was found to accumulate in brain tissues of ALS/PDC patients. It is extremely important to establish a reliable animal model that has the comprehensive characteristics of ALS/PDC for studying mechanisms underlying neurodegeneration, and exploring effective therapies. However, very few good animal models that mimic ALS/PDC have been established. In this study, an ideal rat model that mimicked most characteristics of ALS/PDC was established by administering continuous intravenous (i.v.) injections of neurotoxic l-BMAA. Based on the data obtained, it was demonstrated that continuous i.v. injections of l-BMAA induced mitochondrial morphology and structural changes, astrogliosis, motor neuronal death, and other relative functional changes, which led to the overexpression of pro-inflammatory cytokines cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α), and resulted in the upregulation of glycogen synthase kinase-3 (GSK3), downregulation of astrocytic glutamate transporter-1 (GLT-1), accumulation of microtubule-associated protein tau and cytosolic aggregates of TAR DNA-binding protein-43 (TDP-43) in degenerating motor neurons. These results suggest that this model could be used as a useful tool for the mechanistic and therapeutic study of ALS/PDC.

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Morphometric and neurochemical alterations found in l-BMAA treated rats

Cited by 25 publications

References 80 publications

Quantitative proteomics analysis of zebrafish exposed to sub-lethal dosages of β-methyl-amino-L-alanine (BMAA)

Quantitative proteomics analysis of zebrafish exposed to sub-lethal dosages of β-methyl-amino-L-alanine (BMAA)

Small GSK-3 Inhibitor Shows Efficacy in a Motor Neuron Disease Murine Model Modulating Autophagy

Intravenous injection of l-BMAA induces a rat model with comprehensive characteristics of amyotrophic lateral sclerosis/Parkinson–dementia complex

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