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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
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.
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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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