FOXO protects against age-progressive axonal degeneration. Academic Article uri icon

Overview

abstract

  • Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system-specific deletion of Foxo transcription factors in mice accelerates aging-related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle-aged Foxo knockout mice that are typically only observed in very old wild-type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve-specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself.

publication date

  • November 26, 2017

Research

keywords

  • Axons
  • Forkhead Transcription Factors

Identity

PubMed Central ID

  • PMC5771393

Scopus Document Identifier

  • 85035022192

Digital Object Identifier (DOI)

  • 10.1002/(ISSN)1526-968X

PubMed ID

  • 29178390

Additional Document Info

volume

  • 17

issue

  • 1