p73 regulates neurodegeneration and phospho-tau accumulation during aging and Alzheimer's disease |
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Authors: | Wetzel Monica K Naska Sibel Laliberté Christine L Rymar Vladimir V Fujitani Masashi Biernaskie Jeffrey A Cole Christy J Lerch Jason P Spring Shoshana Wang S-H Frankland Paul W Henkelman R Mark Josselyn Sheena A Sadikot Abbas F Miller Freda D Kaplan David R |
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Affiliation: | Cell Biology, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A2B4, Canada. |
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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. |
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