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

ABSTRACT: Non-protein amino acid beta-N-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-?B) and tumor necrosis factor-alpha (TNF-?), 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.

SUBMITTER: Tian KW

PROVIDER: S-EPMC6060832 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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

Tian Ke-Wei KW Jiang Hong H Wang Bei-Bei BB Zhang Fan F Han Shu S

Toxicology research 20151110 1

Non-protein amino acid beta-<i>N</i>-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 ...[more]

PMID: 30090328

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Project description:Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.

Dataset Information

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

Publications

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

Similar Datasets

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