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RNA Interference of Human α-Synuclein in Mouse
α-Synuclein is postulated to play a key role in the pathogenesis of Parkinson’s disease (PD). Aggregates of α-synuclein contribute to neurodegeneration and cell death in humans and in mouse models of PD. Here, we use virally mediated RNA interference to knockdown human α-synuclein in mice. We used a...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5281542/ https://www.ncbi.nlm.nih.gov/pubmed/28197125 http://dx.doi.org/10.3389/fneur.2017.00013 |
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author | Kim, Young-Cho Miller, Adam Lins, Livia C. R. F. Han, Sang-Woo Keiser, Megan S. Boudreau, Ryan L. Davidson, Beverly L. Narayanan, Nandakumar S. |
author_facet | Kim, Young-Cho Miller, Adam Lins, Livia C. R. F. Han, Sang-Woo Keiser, Megan S. Boudreau, Ryan L. Davidson, Beverly L. Narayanan, Nandakumar S. |
author_sort | Kim, Young-Cho |
collection | PubMed |
description | α-Synuclein is postulated to play a key role in the pathogenesis of Parkinson’s disease (PD). Aggregates of α-synuclein contribute to neurodegeneration and cell death in humans and in mouse models of PD. Here, we use virally mediated RNA interference to knockdown human α-synuclein in mice. We used an siRNA design algorithm to identify eight siRNA sequences with minimal off-targeting potential. One RNA-interference sequence (miSyn4) showed maximal protein knockdown potential in vitro. We then designed AAV vectors expressing miSyn4 and injected them into the mouse substantia nigra. miSyn4 was robustly expressed and did not detectably change dopamine neurons, glial proliferation, or mouse behavior. We then injected AAV2-miSyn4 into Thy1-hSNCA mice over expressing α-synuclein and found decreased human α-synuclein (hSNCA) in both midbrain and cortex. In separate mice, co-injection of AAV2-hSNCA and AAV2-miSyn4 demonstrated decreased hSNCA expression and rescue of hSNCA-mediated behavioral deficits. These data suggest that virally mediated RNA interference can knockdown hSNCA in vivo, which could be helpful for future therapies targeting human α-synuclein. |
format | Online Article Text |
id | pubmed-5281542 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-52815422017-02-14 RNA Interference of Human α-Synuclein in Mouse Kim, Young-Cho Miller, Adam Lins, Livia C. R. F. Han, Sang-Woo Keiser, Megan S. Boudreau, Ryan L. Davidson, Beverly L. Narayanan, Nandakumar S. Front Neurol Neuroscience α-Synuclein is postulated to play a key role in the pathogenesis of Parkinson’s disease (PD). Aggregates of α-synuclein contribute to neurodegeneration and cell death in humans and in mouse models of PD. Here, we use virally mediated RNA interference to knockdown human α-synuclein in mice. We used an siRNA design algorithm to identify eight siRNA sequences with minimal off-targeting potential. One RNA-interference sequence (miSyn4) showed maximal protein knockdown potential in vitro. We then designed AAV vectors expressing miSyn4 and injected them into the mouse substantia nigra. miSyn4 was robustly expressed and did not detectably change dopamine neurons, glial proliferation, or mouse behavior. We then injected AAV2-miSyn4 into Thy1-hSNCA mice over expressing α-synuclein and found decreased human α-synuclein (hSNCA) in both midbrain and cortex. In separate mice, co-injection of AAV2-hSNCA and AAV2-miSyn4 demonstrated decreased hSNCA expression and rescue of hSNCA-mediated behavioral deficits. These data suggest that virally mediated RNA interference can knockdown hSNCA in vivo, which could be helpful for future therapies targeting human α-synuclein. Frontiers Media S.A. 2017-01-31 /pmc/articles/PMC5281542/ /pubmed/28197125 http://dx.doi.org/10.3389/fneur.2017.00013 Text en Copyright © 2017 Kim, Miller, Lins, Han, Keiser, Boudreau, Davidson and Narayanan. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Kim, Young-Cho Miller, Adam Lins, Livia C. R. F. Han, Sang-Woo Keiser, Megan S. Boudreau, Ryan L. Davidson, Beverly L. Narayanan, Nandakumar S. RNA Interference of Human α-Synuclein in Mouse |
title | RNA Interference of Human α-Synuclein in Mouse |
title_full | RNA Interference of Human α-Synuclein in Mouse |
title_fullStr | RNA Interference of Human α-Synuclein in Mouse |
title_full_unstemmed | RNA Interference of Human α-Synuclein in Mouse |
title_short | RNA Interference of Human α-Synuclein in Mouse |
title_sort | rna interference of human α-synuclein in mouse |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5281542/ https://www.ncbi.nlm.nih.gov/pubmed/28197125 http://dx.doi.org/10.3389/fneur.2017.00013 |
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