Title | Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | J Babu R, M Seibenhener L, Peng J, Strom A-L, Kemppainen R, Cox N, Zhu H, Wooten MC, Diaz-Meco MT, Moscat J, Wooten MW |
Journal | J Neurochem |
Volume | 106 |
Issue | 1 |
Pagination | 107-20 |
Date Published | 2008 Jul |
ISSN | 1471-4159 |
Keywords | Adaptor Proteins, Signal Transducing, Aging, Animals, Brain, Brain-Derived Neurotrophic Factor, Disease Models, Animal, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Heat-Shock Proteins, Humans, JNK Mitogen-Activated Protein Kinases, Metabolic Syndrome, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Molecular Chaperones, Nerve Degeneration, Neurofibrillary Tangles, Neurons, Obesity, Phosphorylation, Proto-Oncogene Proteins c-akt, Sequestosome-1 Protein, Signal Transduction, Solubility, tau Proteins |
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. |
DOI | 10.1111/j.1471-4159.2008.05340.x |
Alternate Journal | J Neurochem |
PubMed ID | 18346206 |
Grant List | NS-33661 / NS / NINDS NIH HHS / United States |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.