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Lipid modulators of PP2A activity are efficacious in models of neurodegenerative disorders
Author(s) -
Stock Jeffry B
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.954.3
Subject(s) - protein phosphatase 2 , neuroprotection , phosphatase , demethylase , hyperphosphorylation , pharmacology , disease , methylation , chemistry , medicine , biochemistry , biology , kinase , epigenetics , enzyme , gene
Hyperphosphorylation of tau in Alzheimer's Disease (AD) and α‐synuclein in Parkinson's Disease (PD) play a central role in disease progression and pathology. Use of kinase inhibitors to reverse these processes has been ineffective. Phosphatase activation is an alternative approach. The major neuronal protein phosphatase, PP2A, is regulated by reversible carboxyl methylation. Deficiencies in PP2A methylation have previously been linked to AD, providing a potential target mechanism for therapeutic intervention through inhibition of the PP2A demethylase, PME‐1. Lipid mediators have been identified that enhance PP2A methylation by inhibiting PME‐1 activity. The presence of these lipids in certain botanical extracts is consistent with epidemiological evidence of neuroprotective efficacy. Preliminary results indicate that in mice, oral administration of a naturally occurring serotonin derivative found in coffee, eicosenoyl‐5‐hydroxytryptamide (EHT), blocks PP2A demethylation and reduces P‐tau and P‐α‐syn in animal models for AD and PD. These data support the notion that dietary lipids that modulate PP2A may be useful for the prevention and treatment of neurodegenerative disorders.