title: Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice.
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.
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Roberta
authors.initials: R
authors.lastname: Marongiu
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Margarita
authors.initials: M
authors.lastname: Arango-Lievano
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Sciences, Lund University, 221 00 Lund, Sweden;
authors.forename: Veronica
authors.initials: V
authors.lastname: Francardo
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Peter
authors.initials: P
authors.lastname: Morgenstern
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden;
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Sciences, Lund University, 221 00 Lund, Sweden;
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden;
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065 greengard@rockefeller.edu mik2002@med.cornell.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065; greengard@rockefeller.edu mik2002@med.cornell.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000235:genetics*; D003342:Corpus Striatum / Q000502:physiology*; D020820:Dyskinesias / Q000503:physiopathology*; D015316:Genetic Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D020734:Parkinsonian Disorders / Q000503:physiopathology* / Q000628:therapy; D009418:S100 Proteins / Q000235:genetics*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10
keywords: Parkinson's disease; dyskinesia; gene therapy; p11; striatum