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

Mohammad Arif; Syed Faraz Kazim; Inge Grundke-IqbalRalph M. GarrutoKhalid Iqbal

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

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

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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 inwhich 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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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第3期|1144-1149|共6页
作者
Mohammad Arif; Syed Faraz Kazim; Inge Grundke-IqbalRalph M. GarrutoKhalid Iqbal;
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作者单位

Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314;

Graduate Program in Biomedical Anthropology, Departments of Anthropology and Biological Sciences, Binghamton University, State University of New York, Binghamton, NY 13902;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Alzheimer's disease; amyotrophic lateral sclerosis; tauopathies; tau phosphorylation; cycad;

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

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