Oncotarget

Research Papers: Pathology:

Loss of NEDD4 contributes to RTP801 elevation and neuron toxicity: implications for Parkinson’s disease

Mercè Canal, Núria Martín-Flores, Leticia Pérez-Sisqués, Joan Romaní-Aumedes, Bekir Altas, Heng-Ye Man, Hiroshi Kawabe, Jordi Alberch and Cristina Malagelada _

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Oncotarget. 2016; 7:58813-58831. https://doi.org/10.18632/oncotarget.11020

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Abstract

Mercè Canal1,5, Núria Martín-Flores1,5, Leticia Pérez-Sisqués1,5, Joan Romaní-Aumedes1,5, Bekir Altas2, Heng-Ye Man3, Hiroshi Kawabe2, Jordi Alberch1,4,5 and Cristina Malagelada1,5

1 Department of Biomedicine, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain

2 Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany

3 Department of Biology, Pharmacology and Experimental Therapeutics, Boston University, Boston, Massachusetts, United States of America

4 IDIBAPS-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Catalonia, Spain

5 Institut de Neurociències, Universitat de Barcelona, Barcelona, Catalonia, Spain

Correspondence to:

Cristina Malagelada, email:

Keywords: Parkinson’s disease, neurodegeneration, lysosome, NEDD4, ubiquitin, Pathology Section

Received: May 23, 2016 Accepted: July 22, 2016 Published: August 02, 2016

Abstract

Parkinson’s disease (PD) is a disorder characterized by the degeneration of certain neuronal populations in the central and peripheral nervous system. One of the hallmarks of the disease is the toxic accumulation of proteins within susceptible neurons due to major impairment in the degradation/clearance protein systems.

RTP801 is a pro-apoptotic protein that is sufficient and necessary to induce neuronal death in cellular and animal models of PD. RTP801 is also upregulated in sporadic and parkin mutant PD brains. Here, we report the role of NEDD4, an E3 ligase involved in α-synuclein degradation and PD pathogenesis, in the regulation of RTP801 protein levels and toxicity. NEDD4 polyubiquitinates RTP801 in a cell-free system and in cellular cultures, and they interact physically. NEDD4 conjugates K63-ubiquitin chains to RTP801 and targets it for degradation. NEDD4 regulates RTP801 protein levels in both cultured cells and in the brain tissue. NEDD4 levels are diminished in nigral neurons from human PD brains. Interestingly, neurotoxin 6-OHDA decreases dramatically NEDD4 protein expression but elevates RTP801 protein levels. Moreover, NEDD4 protects neuronal PC12 cells from both 6-OHDA and RTP801-induced toxicity. In primary cortical neurons, NEDD4 knockdown toxicity is mediated by RTP801 since the double knockdown of RTP801 and NEDD4 abrogates the loss of phospho Ser473-Akt and the appearance of caspase-cleaved spectrin fragments.

Thus, NEDD4 ligase regulates RTP801 and is sensitive to PD-associated oxidative stress. This suggests that NEDD4 loss of function in PD could contribute importantly into neuronal death by elevating RTP801.


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