Identification of G-protein coupled receptor kinase 2 in paired helical filaments and neurofibrillary tangles.
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.
Takahashi
Makio
M
Neuroinflammation Research Laboratories, Department of Psychiatry, Mount Sinai School of Medicine and the James J. Peters Veteran Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA.
Uchikado
Hirotake
H
Caprotti
Domenico
D
Weidenheim
Karen M
KM
Dickson
Dennis W
DW
Ksiezak-Reding
Hanna
H
Pasinetti
Giulio M
GM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; D006801:Humans; D016631:Lewy Bodies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020961:Lewy Body Disease / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D020774:Pick Disease of the Brain / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013494:Supranuclear Palsy, Progressive / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D051844:alpha-Synuclein; D016875:tau Proteins; D017346:Protein Serine-Threonine Kinases; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human