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Title: Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson"s disease
Author: Romaní Aumedes, Joan
Canal de la Iglesia, Mercè
Martín-Flores, Núria
Sun, X.
Pérez Fernández, V.
Wewering, S.
Fernández Santiago, Rubén
Ezquerra, Mario
Pont Sunyer, Claustre
Lafuente, Amàlia, 1952-
Alberch i Vié, Jordi
Luebbert, H.
Tolosa, Eduardo
Levy, O.
Greene, L. A.
Malagelada Grau, Cristina
Keywords: Neurologia
Malaltia de Parkinson
Mort cerebral
Parkinson's disease
Brain death
Issue Date: 7-Jul-2014
Publisher: Nature Publishing Group
Abstract: Mutations in the PARK2 gene are associated with an autosomal recessive form of juvenile parkinsonism (AR-JP). These mutations affect parkin solubility and impair its E3 ligase activity, leading to a toxic accumulation of proteins within susceptible neurons that results in a slow but progressive neuronal degeneration and cell death. Here, we report that RTP801/REDD1, a pro-apoptotic negative regulator of survival kinases mTOR and Akt, is one of such parkin substrates. We observed that parkin knockdown elevated RTP801 in sympathetic neurons and neuronal PC12 cells, whereas ectopic parkin enhanced RTP801 poly-ubiquitination and proteasomal degradation. In parkin knockout mouse brains and in human fibroblasts from AR-JP patients with parkin mutations, RTP801 levels were elevated. Moreover, in human postmortem PD brains with mutated parkin, nigral neurons were highly positive for RTP801. Further consistent with the idea that RTP801 is a substrate for parkin, the two endogenous proteins interacted in reciprocal co-immunoprecipitates of cell lysates. A potential physiological role for parkin-mediated RTP801 degradation is indicated by observations that parkin protects neuronal cells from death caused by RTP801 overexpression by mediating its degradation, whereas parkin knockdown exacerbates such death. Similarly, parkin knockdown enhanced RTP801 induction in neuronal cells exposed to the Parkinson's disease mimetic 6-hydroxydopamine and increased sensitivity to this toxin. This response to parkin loss of function appeared to be mediated by RTP801 as it was abolished by RTP801 knockdown. Taken together these results indicate that RTP801 is a novel parkin substrate that may contribute to neurodegeneration caused by loss of parkin expression or activity.
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It is part of: Cell Death and Disease, 2014
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ISSN: 2041-4889
Appears in Collections:Articles publicats en revistes (Fonaments Clínics)
Publicacions de projectes de recerca finançats per la UE

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