Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease
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 neur...
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Nature Publishing Group
2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454308/ |
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pubmed-44543082015-06-15 Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease Romaní-Aumedes, J Canal, M Martín-Flores, N Sun, X Pérez-Fernández, V Wewering, S Fernández-Santiago, R Ezquerra, M Pont-Sunyer, C Lafuente, A Alberch, J Luebbert, H Tolosa, E Levy, O A Greene, L A Malagelada, C Original Article 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. Nature Publishing Group 2014-08 2014-08-07 /pmc/articles/PMC4454308/ /pubmed/25101677 http://dx.doi.org/10.1038/cddis.2014.333 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/3.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Romaní-Aumedes, J Canal, M Martín-Flores, N Sun, X Pérez-Fernández, V Wewering, S Fernández-Santiago, R Ezquerra, M Pont-Sunyer, C Lafuente, A Alberch, J Luebbert, H Tolosa, E Levy, O A Greene, L A Malagelada, C |
| spellingShingle |
Romaní-Aumedes, J Canal, M Martín-Flores, N Sun, X Pérez-Fernández, V Wewering, S Fernández-Santiago, R Ezquerra, M Pont-Sunyer, C Lafuente, A Alberch, J Luebbert, H Tolosa, E Levy, O A Greene, L A Malagelada, C Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease |
| author_facet |
Romaní-Aumedes, J Canal, M Martín-Flores, N Sun, X Pérez-Fernández, V Wewering, S Fernández-Santiago, R Ezquerra, M Pont-Sunyer, C Lafuente, A Alberch, J Luebbert, H Tolosa, E Levy, O A Greene, L A Malagelada, C |
| author_sort |
Romaní-Aumedes, J |
| title |
Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease |
| title_short |
Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease |
| title_full |
Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease |
| title_fullStr |
Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease |
| title_full_unstemmed |
Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease |
| title_sort |
parkin loss of function contributes to rtp801 elevation and neurodegeneration in parkinson's disease |
| description |
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. |
| publisher |
Nature Publishing Group |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454308/ |
| _version_ |
1613231407033745408 |