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- 저자 : Locasale, Jason W. (검색결과 1 건)
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FOXO protects against age‐progressive axonal degeneration
Hwang, Inah,Oh, Hwanhee,Santo, Evan,Kim, Do‐,Yeon,Chen, John W.,Bronson, Roderick T.,Locasale, Jason W.,Na, Yoonmi,Lee, Jaclyn,Reed, Stewart,Toth, Miklos,Yu, Wai H.,Muller, Florian L.,Paik, Jihy John Wiley and Sons Inc. 2018 AGING CELL Vol.17 No.1
<P><B>Summary</B></P><P>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 <I>Foxo</I> 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 <I>Foxo</I> 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 <I>Foxo</I> 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 <I>Foxo</I> 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.</P>
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