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

TitleGene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice.
Publication TypeJournal Article
Year of Publication2016
AuthorsMarongiu R, Arango-Lievano M, Francardo V, Morgenstern P, Zhang X, M Cenci A, Svenningsson P, Greengard P, Kaplitt MG
JournalProc Natl Acad Sci U S A
Volume113
Issue5
Pagination1423-8
Date Published2016 Feb 02
ISSN1091-6490
KeywordsAnimals, Annexin A2, Corpus Striatum, Dyskinesias, Genetic Therapy, Mice, Mice, Inbred C57BL, Motor Activity, Parkinsonian Disorders, S100 Proteins
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.

DOI10.1073/pnas.1524387113
Alternate JournalProc Natl Acad Sci U S A
PubMed ID26787858
PubMed Central IDPMC4747714