title: The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals.
abstract: Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine.
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Mihaela A
authors.initials: MA
authors.lastname: Stavarache
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Musatov
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Marlon
authors.initials: M
authors.lastname: McGill
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Vernov
authors.affiliation: Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: mik2002@med.cornell.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D000229:Dependovirus; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D005822:Genetic Vectors; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism
chemical_list: C000607792:DRD2 protein, rat; D018491:Dopamine Agonists; D034741:RNA, Small Interfering; D017448:Receptors, Dopamine D2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D004298:Dopamine
keywords: AAV; Dopamine; PTEN; Parkinson's disease; Striatum