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Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice.

Marongiu, Roberta; Arango-Lievano, Margarita; Francardo, Veronica LU ; Morgenstern, Peter; Zhang, Xiaoqun; Cenci Nilsson, Angela LU ; Svenningsson, Per; Greengard, Paul and Kaplitt, Michael G (2016) In Proceedings of the National Academy of Sciences 113(5). p.1423-1428
Abstract
Complications of dopamine replacement for Parkinson's disease (PD) can limit therapeutic options, leading to interest in identifying novel pathways that can be exploited to improve treatment. p11 (S100A10) is a cellular scaffold protein that binds to and potentiates the activity of various ion channels and neurotransmitter receptors. We have previously reported that p11 can influence ventral striatal function in models of depression and drug addiction, and thus we hypothesized that dorsal striatal p11 might mediate motor function and drug responses in parkinsonian mice. To focally inhibit p11 expression in the dorsal striatum, we injected an adeno-associated virus (AAV) vector producing a short hairpin RNA (AAV.sh.p11). This intervention... (More)
Complications of dopamine replacement for Parkinson's disease (PD) can limit therapeutic options, leading to interest in identifying novel pathways that can be exploited to improve treatment. p11 (S100A10) is a cellular scaffold protein that binds to and potentiates the activity of various ion channels and neurotransmitter receptors. We have previously reported that p11 can influence ventral striatal function in models of depression and drug addiction, and thus we hypothesized that dorsal striatal p11 might mediate motor function and drug responses in parkinsonian mice. To focally inhibit p11 expression in the dorsal striatum, we injected an adeno-associated virus (AAV) vector producing a short hairpin RNA (AAV.sh.p11). This intervention reduced the impairment in motor function on forced tasks, such as rotarod and treadmill tests, caused by substantia nigra lesioning in mice. Measures of spontaneous movement and gait in an open-field test declined as expected in control lesioned mice, whereas AAV.sh.p11 mice remained at or near normal baseline. Mice with unilateral lesions were then challenged with l-dopa (levodopa) and various dopamine receptor agonists, and resulting rotational behaviors were significantly reduced after ipsilateral inhibition of dorsal striatal p11 expression. Finally, p11 knockdown in the dorsal striatum dramatically reduced l-dopa-induced abnormal involuntary movements compared with control mice. These data indicate that focal inhibition of p11 action in the dorsal striatum could be a promising PD therapeutic target to improve motor function while reducing l-dopa-induced dyskinesias. (Less)
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Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
113
issue
5
pages
1423 - 1428
publisher
National Acad Sciences
external identifiers
  • pmid:26787858
  • scopus:84956629890
  • wos:000369085100084
ISSN
1091-6490
DOI
10.1073/pnas.1524387113
language
English
LU publication?
yes
id
d9f52f85-7e3a-4e66-9271-00aca09716f0 (old id 8576862)
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http://www.ncbi.nlm.nih.gov/pubmed/26787858?dopt=Abstract
date added to LUP
2016-02-03 20:28:22
date last changed
2017-08-20 04:37:42
@article{d9f52f85-7e3a-4e66-9271-00aca09716f0,
  abstract     = {Complications of dopamine replacement for Parkinson's disease (PD) can limit therapeutic options, leading to interest in identifying novel pathways that can be exploited to improve treatment. p11 (S100A10) is a cellular scaffold protein that binds to and potentiates the activity of various ion channels and neurotransmitter receptors. We have previously reported that p11 can influence ventral striatal function in models of depression and drug addiction, and thus we hypothesized that dorsal striatal p11 might mediate motor function and drug responses in parkinsonian mice. To focally inhibit p11 expression in the dorsal striatum, we injected an adeno-associated virus (AAV) vector producing a short hairpin RNA (AAV.sh.p11). This intervention reduced the impairment in motor function on forced tasks, such as rotarod and treadmill tests, caused by substantia nigra lesioning in mice. Measures of spontaneous movement and gait in an open-field test declined as expected in control lesioned mice, whereas AAV.sh.p11 mice remained at or near normal baseline. Mice with unilateral lesions were then challenged with l-dopa (levodopa) and various dopamine receptor agonists, and resulting rotational behaviors were significantly reduced after ipsilateral inhibition of dorsal striatal p11 expression. Finally, p11 knockdown in the dorsal striatum dramatically reduced l-dopa-induced abnormal involuntary movements compared with control mice. These data indicate that focal inhibition of p11 action in the dorsal striatum could be a promising PD therapeutic target to improve motor function while reducing l-dopa-induced dyskinesias.},
  author       = {Marongiu, Roberta and Arango-Lievano, Margarita and Francardo, Veronica and Morgenstern, Peter and Zhang, Xiaoqun and Cenci Nilsson, Angela and Svenningsson, Per and Greengard, Paul and Kaplitt, Michael G},
  issn         = {1091-6490},
  language     = {eng},
  month        = {01},
  number       = {5},
  pages        = {1423--1428},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice.},
  url          = {http://dx.doi.org/10.1073/pnas.1524387113},
  volume       = {113},
  year         = {2016},
}