Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration

Young Don Kwak, Bin Wang, Jing Jing Li, Ruishan Wang, Qiyue Deng, Shiyong Diao, Yaomin Chen, Raymond Xu, Eliezer Masliah, Huaxi Xu, Jung Joon Sung, Francesca-Fang Liao

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Abstract

The importance of ubiquitin E3 ligases in neurodegeneration is being increasingly recognized. The crucial role of NEDD4-1 in neural development is well appreciated; however, its role in neurodegeneration remains unexplored. Herein, we report increased NEDD4-1 expression in the degenerated tissues of several major neurodegenerative diseases. Moreover, its expression is upregulated in cultured neurons in response to various neurotoxins, including zinc and hydrogen superoxide, via transcriptional activation likely mediated by the reactive oxygen species (ROS)-responsive FOXM1B. Reduced protein levels of the insulin-like growth factor receptor (IGF-1Rβ) were observed as a consequence of upregulated NEDD4-1 via the ubiquitin-proteasome system. Overexpression of a familial mutant form of superoxide dismutase 1 (SOD1) (G93A) in neuroblastoma cells resulted in a similar reduction of IGF-1Rβ protein. This inverse correla-tion between NEDD4-1 and IGF-1Rβ was also observed in the cortex and spinal cords of mutant (G93A) SOD1 transgenic mice at a presymptomatic age, which was similarly induced by in vivo-administered zinc in wild-type C57BL/6 mice. Furthermore, histochemistry reveals markedly increased NEDD4-1 immunoreactivity in the degenerating/degenerated motor neurons in the lumbar anterior horn of the spinal cord, suggesting a direct causative role for NEDD4-1 in neurodegeneration. Indeed, downregulation of NEDD4-1 by shRNA or overexpression of a catalytically inactive form rescued neurons from zinc-induced cell death. Similarly, neurons with a NEDD4-1 haplo-type are more resistant to apoptosis, largely due to expression of higher levels of IGF-1Rβ.Together, our work identifies a novel molecular mechanism for ROS-upregulated NEDD4-1 and the subsequently reduced IGF-1Rβ signaling in neurodegeneration.

Original languageEnglish (US)
Pages (from-to)10971-10981
Number of pages11
JournalJournal of Neuroscience
Volume32
Issue number32
DOIs
StatePublished - Aug 8 2012

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IGF Type 1 Receptor
Ubiquitin-Protein Ligases
Zinc
Oxidative Stress
Up-Regulation
Neurons
Reactive Oxygen Species
Somatomedin Receptors
Proteins
Neurotoxins
Motor Neurons
Proteasome Endopeptidase Complex
Ubiquitin
Neuroblastoma
Insulin-Like Growth Factor I
Inbred C57BL Mouse
Superoxides
Neurodegenerative Diseases
Small Interfering RNA
Transgenic Mice

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration. / Kwak, Young Don; Wang, Bin; Li, Jing Jing; Wang, Ruishan; Deng, Qiyue; Diao, Shiyong; Chen, Yaomin; Xu, Raymond; Masliah, Eliezer; Xu, Huaxi; Sung, Jung Joon; Liao, Francesca-Fang.

In: Journal of Neuroscience, Vol. 32, No. 32, 08.08.2012, p. 10971-10981.

Research output: Contribution to journalArticle

Kwak, YD, Wang, B, Li, JJ, Wang, R, Deng, Q, Diao, S, Chen, Y, Xu, R, Masliah, E, Xu, H, Sung, JJ & Liao, F-F 2012, 'Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration', Journal of Neuroscience, vol. 32, no. 32, pp. 10971-10981. https://doi.org/10.1523/JNEUROSCI.1836-12.2012
Kwak, Young Don ; Wang, Bin ; Li, Jing Jing ; Wang, Ruishan ; Deng, Qiyue ; Diao, Shiyong ; Chen, Yaomin ; Xu, Raymond ; Masliah, Eliezer ; Xu, Huaxi ; Sung, Jung Joon ; Liao, Francesca-Fang. / Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 32. pp. 10971-10981.
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