RGD Reference Report - Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam. - Rat Genome Database

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

Authors: Arif, M  Kazim, SF  Grundke-Iqbal, I  Garruto, RM  Iqbal, K 
Citation: Arif M, etal., Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1144-9. doi: 10.1073/pnas.1322614111. Epub 2014 Jan 6.
RGD ID: 8693390
Pubmed: PMID:24395787   (View Abstract at PubMed)
PMCID: PMC3903234   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1322614111   (Journal Full-text)

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. beta-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinson's disease  IEP 8693390protein:decreased tyrosine phosphorylation:brain (human)RGD 
Parkinson's disease  ISOPPP2CA (Homo sapiens)8693390; 8693390protein:decreased tyrosine phosphorylation:brain (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ppp2ca  (protein phosphatase 2 catalytic subunit alpha)

Genes (Mus musculus)
Ppp2ca  (protein phosphatase 2 (formerly 2A), catalytic subunit, alpha isoform)

Genes (Homo sapiens)
PPP2CA  (protein phosphatase 2 catalytic subunit alpha)


Additional Information