Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration

J. Ramesh Babu, M. Lamar Seibenhener, Junmin Peng, Anna Lena Strom, Robert Kemppainen, Nancy Cox, Haining Zhu, Michael C. Wooten, María T. Diaz-Meco, Jorge Moscat, Marie W. Wooten

Research output: Contribution to journalArticlepeer-review

180 Scopus citations

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 3β, 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.

Original languageEnglish (US)
Pages (from-to)107-120
Number of pages14
JournalJournal of neurochemistry
Volume106
Issue number1
DOIs
StatePublished - Jul 2008
Externally publishedYes

Keywords

  • Aging
  • Alzheimer's disease
  • Anxiety
  • Obesity
  • p62
  • Tau

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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