The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-10-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115300176 |
| _version_ | 1819159865819398144 |
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| author | Mihaela A. Stavarache Sergei Musatov Marlon McGill Mary Vernov Michael G. Kaplitt |
| author_facet | Mihaela A. Stavarache Sergei Musatov Marlon McGill Mary Vernov Michael G. Kaplitt |
| author_sort | Mihaela A. Stavarache |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T16:47:21Z |
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| id | doaj.art-c163f4f97b2342e6b90375b40bfaf359 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T16:47:21Z |
| publishDate | 2015-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-c163f4f97b2342e6b90375b40bfaf3592022-12-21T18:19:42ZengElsevierNeurobiology of Disease1095-953X2015-10-0182487494The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animalsMihaela A. Stavarache0Sergei Musatov1Marlon McGill2Mary Vernov3Michael G. Kaplitt4Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USALaboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USALaboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USALaboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USACorresponding author at: Department of Neurological Surgery, Weill Cornell Medical College, 525 East 68th St., Box 99, New York, NY 10065, USA.; Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10065, USAPhosphatase 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.http://www.sciencedirect.com/science/article/pii/S0969996115300176PTENDopamineStriatumParkinson's diseaseAAV |
| spellingShingle | Mihaela A. Stavarache Sergei Musatov Marlon McGill Mary Vernov Michael G. Kaplitt The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals Neurobiology of Disease PTEN Dopamine Striatum Parkinson's disease AAV |
| title | The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals |
| title_full | The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals |
| title_fullStr | The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals |
| title_full_unstemmed | The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals |
| title_short | The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals |
| title_sort | tumor suppressor pten regulates motor responses to striatal dopamine in normal and parkinsonian animals |
| topic | PTEN Dopamine Striatum Parkinson's disease AAV |
| url | http://www.sciencedirect.com/science/article/pii/S0969996115300176 |
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