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.
Highlights
In Parkinson’s disease (PD), the mechanisms by which specific subpopulations of both central and peripheral neurons degenerate are not yet elucidated [1]
We show that RTP801, a pro-apoptotic protein involved in neuron death in cellular and animal models of PD, is a novel substrate of NEDD4
NEDD4 protein levels are diminished in remaining nigral neurons in human sporadic PD brains
Summary
In Parkinson’s disease (PD), the mechanisms by which specific subpopulations of both central and peripheral neurons degenerate are not yet elucidated [1]. In cellular models of PD, shRNA-mediated RTP801 knockdown is protective toward cell death induced by 6-hydroxydopamine (6OHDA) or MPP+ [6]. RTP801 triggers neuron cell death by a sequential mechanism in which it first inactivates mechanistic target of Rapamycin (mTOR) and as a consequence, inhibits the neuronal survival kinase Akt, which is a substrate of mTOR [6, 7]. Developmentally down-regulated 4 (NEDD4) is one of the most abundant ubiquitin E3 ligases in mammalian neurons [11]. NEDD4 ubiquitinates proteins, targeting them for proteasomal or lysosomal degradation [12]. In a context of PD, NEDD4 protects neurons from alpha synuclein toxicity by ubiquitinating it and mediating its lysosomal degradation [15, 16]. 6-OHDA downregulates NEDD4 in neural cultures and NEDD4 deregulation contributes to toxic elevation of RTP801 in cellular models of PD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
