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 correlation 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 haplotype 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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aged
-
Aged, 80 and over
-
Amyloid beta-Protein Precursor / genetics
-
Analysis of Variance
-
Animals
-
Brain / metabolism
-
Cells, Cultured
-
Cerebral Cortex / pathology
-
Chromatin Immunoprecipitation
-
Embryo, Mammalian
-
Endosomal Sorting Complexes Required for Transport / genetics
-
Endosomal Sorting Complexes Required for Transport / metabolism*
-
Female
-
Forkhead Box Protein M1
-
Forkhead Transcription Factors / metabolism
-
Humans
-
Hydrogen Peroxide / pharmacology
-
In Situ Nick-End Labeling
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Nedd4 Ubiquitin Protein Ligases
-
Neurodegenerative Diseases / etiology
-
Neurodegenerative Diseases / metabolism*
-
Neurodegenerative Diseases / pathology
-
Neurons / drug effects
-
Neurons / metabolism
-
Neurotoxins / pharmacology
-
Oxidative Stress / drug effects
-
Oxidative Stress / physiology*
-
RNA, Small Interfering / metabolism
-
Rats
-
Reactive Oxygen Species / metabolism
-
Receptor, IGF Type 1 / genetics
-
Receptor, IGF Type 1 / metabolism*
-
Spinal Cord / metabolism
-
Spinal Cord / pathology
-
Superoxide Dismutase / genetics
-
Time Factors
-
Transcription Factors / metabolism
-
Transfection
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism*
-
Up-Regulation / drug effects
-
Up-Regulation / physiology*
-
Zinc Sulfate / pharmacology
Substances
-
Amyloid beta-Protein Precursor
-
Endosomal Sorting Complexes Required for Transport
-
FOXM1 protein, human
-
Forkhead Box Protein M1
-
Forkhead Transcription Factors
-
Neurotoxins
-
RNA, Small Interfering
-
Reactive Oxygen Species
-
Transcription Factors
-
Zinc Sulfate
-
Hydrogen Peroxide
-
SOD1 G93A protein
-
Superoxide Dismutase
-
NEDD4L protein, rat
-
Nedd4 Ubiquitin Protein Ligases
-
Nedd4 protein, human
-
Nedd4 protein, rat
-
Nedd4l protein, mouse
-
Ubiquitin-Protein Ligases
-
Receptor, IGF Type 1