WWOX Phosphorylation, Signaling, and Role in Neurodegeneration

Frontiers in Neuroscience
Chan-Chuan LiuNan-Shan Chang

Abstract

Homozygous null mutation of tumor suppressor WWOX/Wwox gene leads to severe neural diseases, metabolic disorders and early death in the newborns of humans, mice and rats. WWOX is frequently downregulated in the hippocampi of patients with Alzheimer's disease (AD). In vitro analysis revealed that knockdown of WWOX protein in neuroblastoma cells results in aggregation of TRAPPC6AΔ, TIAF1, amyloid β, and Tau in a sequential manner. Indeed, TRAPPC6AΔ and TIAF1, but not tau and amyloid β, aggregates are present in the brains of healthy mid-aged individuals. It is reasonable to assume that very slow activation of a protein aggregation cascade starts sequentially with TRAPPC6AΔ and TIAF1 aggregation at mid-ages, then caspase activation and APP de-phosphorylation and degradation, and final accumulation of amyloid β and Tau aggregates in the brains at greater than 70 years old. WWOX binds Tau-hyperphosphorylating enzymes (e.g., GSK-3β) and blocks their functions, thereby supporting neuronal survival and differentiation. As a neuronal protective hormone, 17β-estradiol (E2) binds WWOX at an NSYK motif in the C-terminal SDR (short-chain alcohol dehydrogenase/reductase) domain. In this review, we discuss how WWOX and E2 block protein aggreg...Continue Reading

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Citations

May 20, 2020·Communications Biology·Martina SolaPaolo Paganetti
May 12, 2020·Experimental Biology and Medicine·K KoślaA K Bednarek
Sep 24, 2019·Frontiers in Cellular Neuroscience·Katarzyna KoślaAndrzej K Bednarek
Dec 13, 2019·Molecular Brain·Hyun Jin KimJoung-Hun Kim
Jun 26, 2020·Frontiers in Neuroscience·Michele IacominoVincenzo Salpietro
Nov 17, 2020·Frontiers in Cell and Developmental Biology·Ying-Tsen ChouLi-Jin Hsu
Dec 2, 2020·International Journal of Molecular Sciences·C Marcelo Aldaz, Tabish Hussain
Aug 8, 2021·Cells·Che-Yu HsuNan-Shan Chang

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Methods Mentioned

BETA
dissection
nuclear translocation
transgenic

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