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

Proceedings of the National Academy of Sciences of the United States of America
Roberta MarongiuMichael G Kaplitt

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 ipsil...Continue Reading

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Citations

Jan 21, 2016·Proceedings of the National Academy of Sciences of the United States of America·Nicoletta SchintuPer Svenningsson
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Holly GreenPer Svenningsson
Dec 9, 2017·Movement Disorders : Official Journal of the Movement Disorder Society·Barbara PicconiPaolo Calabresi

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