title: Tau pathology involves protein phosphatase 2A in parkinsonism-dementia of Guam.
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.
authors.affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Arif
authors.forename: Syed Faraz
authors.initials: SF
authors.lastname: Kazim
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Garruto
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C578937:Grm5 protein, rat; D009498:Neurotoxins; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D016875:tau Proteins; D014443:Tyrosine; D019061:src-Family Kinases; D054648:Protein Phosphatase 2
keywords: Alzheimer's disease; amyotrophic lateral sclerosis; cycad; tau phosphorylation; tauopathies