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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Aging / genetics
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Aging / metabolism
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Animals
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Brain / metabolism*
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Brain / pathology
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Brain / physiopathology
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Brain-Derived Neurotrophic Factor / metabolism
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Disease Models, Animal
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Heat-Shock Proteins / genetics*
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Metabolic Syndrome / complications
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Metabolic Syndrome / genetics
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Metabolic Syndrome / metabolism
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism
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Molecular Chaperones / genetics*
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Nerve Degeneration / genetics*
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Nerve Degeneration / metabolism
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Nerve Degeneration / physiopathology
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Neurofibrillary Tangles / genetics
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Neurofibrillary Tangles / metabolism
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Neurofibrillary Tangles / pathology
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Neurons / metabolism*
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Neurons / pathology
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Obesity / complications
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Obesity / metabolism
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Obesity / physiopathology
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Sequestosome-1 Protein
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Signal Transduction / physiology
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Solubility
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tau Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Brain-Derived Neurotrophic Factor
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Heat-Shock Proteins
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Molecular Chaperones
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Sequestosome-1 Protein
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Sqstm1 protein, mouse
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tau Proteins
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Glycogen Synthase Kinase 3