ArticleProceedings of the National Academy of Sciences of the United States of America2014
Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 85 citations in OpenAlex.
- Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology.Frontiers in neurology · 2020Pooled it
- Tau pathology is associated with postsynaptic metabotropic glutamate receptor 5 (mGluR5) in early Alzheimer's disease in a sex-specific manner.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review.Molecules (Basel, Switzerland) · 2024Review
- The cycad genotoxin methylazoxymethanol, linked to Guam ALS/PDC, induces transcriptional mutagenesis.Acta neuropathologica communications · 2024Article
- Environmental Neurotoxin β-Microorganisms · 2022Review
- Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis.Neurotoxicity research · 2022Review
- Cyanotoxins and the Nervous System.Toxins · 2021Review
- Review of PP2A Tumor Biology and Antitumor Effects of PP2A Inhibitor LB100 in the Nervous System.Cancers · 2021Review
- Is Exposure to BMAA a Risk Factor for Neurodegenerative Diseases? A Response to a Critical Review of the BMAA Hypothesis.Neurotoxicity research · 2021Article
- Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive and Electrophysiological Impairments in Tg2576 APP Transgenic Mice.Journal of Alzheimer's disease : JAD · 2021Article
- Attenuation of Acute Intracerebral Hemorrhage-Induced Microglial Activation and Neuronal Death Mediated by the Blockade of Metabotropic Glutamate Receptor 5 In Vivo.Neurochemical research · 2020Article
- The impact of proteostasis dysfunction secondary to environmental and genetic causes on neurodegenerative diseases progression and potential therapeutic intervention.Environmental science and pollution research international · 2020Review
- l-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND.Journal of neuropathology and experimental neurology · 2020Article
- To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling.Cellular and molecular life sciences : CMLS · 2019Review
- Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Could Alzheimer's Disease Originate in the Periphery and If So How So?Molecular neurobiology · 2019Review
- BMAA and Neurodegenerative Illness.Neurotoxicity research · 2018Review
- Creating a Simian Model of Guam ALS/PDC Which Reflects Chamorro Lifetime BMAA Exposures.Neurotoxicity research · 2018Article
- Cyanobacterial Neurotoxins: Their Occurrence and Mechanisms of Toxicity.Neurotoxicity research · 2018Review
- L-Serine-Mediated Neuroprotection Includes the Upregulation of the ER Stress Chaperone Protein Disulfide Isomerase (PDI).Neurotoxicity research · 2018Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
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-l-alanine (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 BMAA-induced 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.
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