title: p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer's disease.
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.
authors.affiliation: Cell Biology, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A2B4, Canada.
authors.forename: Monica K
authors.initials: MK
authors.lastname: Wetzel
authors.forename: Sibel
authors.initials: S
authors.lastname: Naska
authors.forename: Christine L
authors.initials: CL
authors.lastname: Laliberté
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Rymar
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujitani
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Biernaskie
authors.forename: Christy J
authors.initials: CJ
authors.lastname: Cole
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
authors.forename: Shoshana
authors.initials: S
authors.lastname: Spring
authors.forename: S-H
authors.initials: SH
authors.lastname: Wang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Sheena A
authors.initials: SA
authors.lastname: Josselyn
authors.forename: Abbas F
authors.initials: AF
authors.lastname: Sadikot
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000367:Age Factors; D000375:Aging; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D005697:Galactosides / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000494:pharmacology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D005697:Galactosides; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C007816:beta-galactoside; D016875:tau Proteins; D048670:MAP Kinase Kinase 4; D010744:Phosphoric Monoester Hydrolases; D010751:Phosphopyruvate Hydratase