RNA Interference of Human α-Synuclein in Mouse

Young-Cho Kim; Adam Miller; Livia C. R. F Lins; Sang-Woo Han; Megan S Keiser; Ryan L Boudreau; Beverly L Davidson; Nandakumar S Narayanan

doi:10.3389/fneur.2017.00013

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RNA Interference of Human α-Synuclein in Mouse

Journal article

Open access

Peer reviewed

RNA Interference of Human α-Synuclein in Mouse

Young-Cho Kim, Adam Miller, Livia C. R. F Lins, Sang-Woo Han, Megan S Keiser, Ryan L Boudreau, Beverly L Davidson and Nandakumar S Narayanan

Frontiers in neurology, Vol.8, pp.13-13

01/31/2017

DOI: 10.3389/fneur.2017.00013

PMCID: PMC5281542

PMID: 28197125

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Abstract

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.

neurodegeneration

Neuroscience

siRNA

RNA interference

α-synuclein

Parkinson’s disease

Details

Title: Subtitle: RNA Interference of Human α-Synuclein in Mouse
Creators: Young-Cho Kim - Department of Neurology, University of Iowa Hospitals and Clinics
Adam Miller - Department of Neurology, University of Iowa Hospitals and Clinics
Livia C. R. F Lins - Department of Neurology, University of Iowa Hospitals and Clinics
Sang-Woo Han - Department of Neurology, University of Iowa Hospitals and Clinics
Megan S Keiser - Children’s Hospital of Philadelphia
Ryan L Boudreau - Department of Internal Medicine, University of Iowa Hospitals and Clinics
Beverly L Davidson - Children’s Hospital of Philadelphia
Nandakumar S Narayanan - Department of Neurology, University of Iowa Hospitals and Clinics
Resource Type: Journal article
Publication Details: Frontiers in neurology, Vol.8, pp.13-13
DOI: 10.3389/fneur.2017.00013
PMID: 28197125
PMCID: PMC5281542
NLM abbreviation: Front Neurol
ISSN: 1664-2295
eISSN: 1664-2295
Publisher: Frontiers Media S.A
Language: English
Date published: 01/31/2017
Academic Unit: Neurology; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984020763902771

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