p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer's disease

Monica K Wetzel; Sibel Naska; Christine L Laliberté; Vladimir V Rymar; Masashi Fujitani; Jeffrey A Biernaskie; Christy J Cole; Jason P Lerch; Shoshana Spring; S-H Wang; Paul W Frankland; R Mark Henkelman; Sheena A Josselyn; Abbas F Sadikot; Freda D Miller; David R Kaplan

doi:10.1016/j.neuron.2008.07.021

p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer's disease

Neuron. 2008 Sep 11;59(5):708-21. doi: 10.1016/j.neuron.2008.07.021.

Authors

Monica K Wetzel¹, Sibel Naska, Christine L Laliberté, Vladimir V Rymar, Masashi Fujitani, Jeffrey A Biernaskie, Christy J Cole, Jason P Lerch, Shoshana Spring, S-H Wang, Paul W Frankland, R Mark Henkelman, Sheena A Josselyn, Abbas F Sadikot, Freda D Miller, David R Kaplan

Affiliation

¹ Cell Biology, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A2B4, Canada.

PMID: 18786355
DOI: 10.1016/j.neuron.2008.07.021

Abstract

The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Aging*
Alzheimer Disease / complications
Alzheimer Disease / genetics
Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Amyloid beta-Protein Precursor / genetics
Analysis of Variance
Animals
Behavior, Animal
Cell Cycle / drug effects
Cell Cycle / genetics
Cell Cycle / physiology
Cells, Cultured
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology*
Disease Models, Animal
Embryo, Mammalian
Exploratory Behavior / drug effects
Exploratory Behavior / physiology
Flow Cytometry
Galactosides / metabolism
MAP Kinase Kinase 4 / metabolism
Magnetic Resonance Imaging / methods
Maze Learning / drug effects
Maze Learning / physiology
Mice
Mice, Transgenic
Microglia / pathology
Mutation / genetics
Neurodegenerative Diseases / etiology*
Neurodegenerative Diseases / pathology
Nuclear Proteins / genetics
Nuclear Proteins / physiology*
Phosphopyruvate Hydratase / metabolism
Phosphoric Monoester Hydrolases / pharmacology
Tumor Protein p73
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / physiology*
tau Proteins / metabolism*

Substances

Amyloid beta-Protein Precursor
DNA-Binding Proteins
Galactosides
Nuclear Proteins
Trp73 protein, mouse
Tumor Protein p73
Tumor Suppressor Proteins
beta-galactoside
tau Proteins
MAP Kinase Kinase 4
Phosphoric Monoester Hydrolases
Phosphopyruvate Hydratase