Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. Academic Article uri icon

Overview

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 date

  • July 1, 2008

Research

keywords

  • Adaptor Proteins, Signal Transducing
  • Brain
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Nerve Degeneration
  • Neurons
  • tau Proteins

Identity

Scopus Document Identifier

  • 45249105920

Digital Object Identifier (DOI)

  • 10.1111/j.1471-4159.2008.05340.x

PubMed ID

  • 18346206

Additional Document Info

volume

  • 106

issue

  • 1