title: Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration.
abstract: The signaling adapter p62 plays a coordinating role in mediating phosphorylation and ubiquitin-dependent trafficking of interacting proteins. However, there is little known about the physiologic role of this protein in brain. Here, we report age-dependent constitutive activation of glycogen synthase kinase 3beta, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration. Biochemical fractionation of p62(-/-) brain led to recovery of aggregated K63-ubiquitinated tau. Loss of p62 was manifested by increased anxiety, depression, loss of working memory, and reduced serum brain-derived neurotrophic factor levels. Our findings reveal a novel role for p62 as a chaperone that regulates tau solubility thereby preventing tau aggregation. This study provides a clear demonstration of an Alzheimer-like phenotype in a mouse model in the absence of expression of human genes carrying mutations in amyloid-beta protein precursor, presenilin, or tau. Thus, these findings provide new insight into manifestation of sporadic Alzheimer disease and the impact of obesity.
authors.affiliation: Department of Biological Sciences, Program in Cellular and Molecular Biosciences, Auburn University, Auburn, Alabama 36849, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ramesh Babu
authors.forename: M
authors.initials: M
authors.lastname: Lamar Seibenhener
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Strom
authors.forename: Robert
authors.initials: R
authors.lastname: Kemppainen
authors.forename: Nancy
authors.initials: N
authors.lastname: Cox
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wooten
authors.forename: María T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Marie W
authors.initials: MW
authors.lastname: Wooten
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D024821:Metabolic Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D038362:Glycogen Synthase Kinase 3