Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52

Chulman Jo, Soner Gundemir, Susanne Pritchard, Youngnam N. Jin, Irfan Rahman and Gail V. W. Johnson ()
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Chulman Jo: University of Rochester Medical Center, University of Rochester, 601 Elmwood Avenue
Soner Gundemir: University of Rochester Medical Center, University of Rochester, 601 Elmwood Avenue
Susanne Pritchard: University of Rochester Medical Center, University of Rochester, 601 Elmwood Avenue
Youngnam N. Jin: University of Rochester Medical Center, University of Rochester, 601 Elmwood Avenue
Irfan Rahman: Lung Biology and Disease Program, University of Rochester Medical Center, University of Rochester, 601 Elmwood Avenue
Gail V. W. Johnson: University of Rochester Medical Center, University of Rochester, 601 Elmwood Avenue

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor in the defence against oxidative stress. Here we provide evidence that activation of the Nrf2 pathway reduces the levels of phosphorylated tau by induction of an autophagy adaptor protein NDP52 (also known as CALCOCO2) in neurons. The expression of NDP52, which we show has three antioxidant response elements (AREs) in its promoter region, is strongly induced by Nrf2, and its overexpression facilitates clearance of phosphorylated tau in the presence of an autophagy stimulator. In Nrf2-knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates in the brains concurrent with decreased levels of NDP52. Moreover, NDP52 associates with phosphorylated tau from brain cortical samples of Alzheimer disease cases, and the amount of phosphorylated tau in sarkosyl-insoluble fractions is inversely proportional to that of NDP52. These results suggest that NDP52 plays a key role in autophagy-mediated degradation of phosphorylated tau in vivo.

Date: 2014
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DOI: 10.1038/ncomms4496

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