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Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse.
Taylor, Tonya N; Potgieter, Dawid; Anwar, Sabina; Senior, Steven L; Janezic, Stephanie; Threlfell, Sarah; Ryan, Brent; Parkkinen, Laura; Deltheil, Thierry; Cioroch, Milena; Livieratos, Achilleas; Oliver, Peter L; Jennings, Katie A; Davies, Kay E; Ansorge, Olaf; Bannerman, David M; Cragg, Stephanie J; Wade-Martins, Richard.
Afiliação
  • Taylor TN; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Potgieter D; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Anwar S; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Senior SL; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Janezic S; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Threlfell S; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Ryan B; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Parkkinen L; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK.
  • Deltheil T; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Cioroch M; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Livieratos A; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
  • Oliver PL; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
  • Jennings KA; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Davies KE; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
  • Ansorge O; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK.
  • Bannerman DM; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Experimental Psychology, University of Oxford, Oxford, UK.
  • Cragg SJ; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
  • Wade-Martins R; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK. Electronic address: richard.wade-martins@dpag.ox.ac.uk.
Neurobiol Dis ; 62: 193-207, 2014 Feb.
Article em En | MEDLINE | ID: mdl-24121116
ABSTRACT
Parkinson's disease (PD) is a neurodegenerative disorder classically characterized by the death of dopamine (DA) neurons in the substantia nigra pars compacta and by intracellular Lewy bodies composed largely of α-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in α-synuclein. To better understand the cell-type specific role of α-synuclein on DA neurotransmission, and the effects of the disease-associated A30P mutation, we generated and studied a novel transgenic model of PD. We expressed the A30P mutant form of human α-synuclein in a spatially-relevant manner from the 111kb SNCA genomic DNA locus on a bacterial artificial chromosome (BAC) insert on a mouse null (Snca-/-) background. The BAC transgenic mice expressed α-synuclein in tyrosine hydroxylase-positive neurons and expression of either A30P α-synuclein or wildtype α-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca-/- animals. A30P α-synuclein mice showed no Lewy body-like aggregation, and did not lose catecholamine neurons in substantia nigra or locus coeruleus. However, using cyclic voltammetry at carbon-fiber microelectrodes we identified a deficit in evoked DA release in the caudate putamen, but not in the nucleus accumbens, of SNCA-A30P Snca-/- mice but no changes to release of another catecholamine, norepinephrine (NE), in the NE-rich ventral bed nucleus of stria terminalis. SNCA-A30P Snca-/- mice had no overt behavioral impairments but exhibited a mild increase in wheel-running. In summary, this refined PD mouse model shows that A30P α-synuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Gânglios da Base / Dopamina / Norepinefrina / Alfa-Sinucleína / Neurônios Dopaminérgicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Neurobiol Dis Assunto da revista: NEUROLOGIA Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Reino Unido
Texto completo
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Gânglios da Base / Dopamina / Norepinefrina / Alfa-Sinucleína / Neurônios Dopaminérgicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Neurobiol Dis Assunto da revista: NEUROLOGIA Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Reino Unido