Abstract
G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixed with Alzheimer disease (AD + LBD). Instead, GRK2 but not GRK5 colocalized with 40% to 50% of neurofibrillary tangles in AD + LBD and AD brains. In disorders with less prominent alpha-synucleinopathy, neuronal and glial fibrillary tau deposits known to contain distinct subsets of tau isoforms were also positive for GRK2. These deposits included tufted astrocytes and coiled bodies in progressive supranuclear palsy, astrocytic plaques in corticobasal degeneration, and Pick bodies in Pick disease. In addition, paired helical filaments isolated from AD and AD + LBD brains were found to immunogold-label for GRK2, suggesting that GRK2 could be a potential tau kinase associated with fibrillary tau. Our studies indicate that GRK2 is a novel component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding. GRK2 may play a role in hyperphosphorylation of tau in tauopathies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Alzheimer Disease / enzymology
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Alzheimer Disease / pathology
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Alzheimer Disease / physiopathology
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Brain / enzymology*
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Brain / pathology
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Brain / physiopathology
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Female
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G-Protein-Coupled Receptor Kinase 2
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G-Protein-Coupled Receptor Kinase 5
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Humans
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Lewy Bodies / enzymology
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Lewy Bodies / genetics
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Lewy Bodies / pathology
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Lewy Body Disease / embryology
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Lewy Body Disease / pathology
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Lewy Body Disease / physiopathology
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Male
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Neurodegenerative Diseases / enzymology*
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Neurodegenerative Diseases / pathology
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Neurodegenerative Diseases / physiopathology
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Neurofibrillary Tangles / enzymology*
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Neurofibrillary Tangles / genetics
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Neurofibrillary Tangles / pathology
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Neuroglia / enzymology
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Neuroglia / pathology
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Neurons / enzymology
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Neurons / pathology
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Phosphorylation
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Pick Disease of the Brain / enzymology
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Pick Disease of the Brain / pathology
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Pick Disease of the Brain / physiopathology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Supranuclear Palsy, Progressive / enzymology
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Supranuclear Palsy, Progressive / pathology
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Supranuclear Palsy, Progressive / physiopathology
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alpha-Synuclein / genetics
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alpha-Synuclein / metabolism
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beta-Adrenergic Receptor Kinases / genetics
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beta-Adrenergic Receptor Kinases / metabolism*
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tau Proteins / genetics
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tau Proteins / metabolism
Substances
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alpha-Synuclein
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tau Proteins
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Protein Serine-Threonine Kinases
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GRK2 protein, human
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beta-Adrenergic Receptor Kinases
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G-Protein-Coupled Receptor Kinase 2
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G-Protein-Coupled Receptor Kinase 5
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GRK5 protein, human