Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression
Parkinson's disease (PD) is characterized by the formation of intracytoplasmic inclusions, which contain α-synuclein (α-syn) protein. While most profound neurodegeneration is seen in the dopamine (DA) synthesizing neurons located in the ventral midbrain, it is unclear why some DA cell groups ar...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2006-09-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996106000933 |
id |
doaj-7e4c4ff985ee448cbecdfabbc6959ad5 |
---|---|
record_format |
Article |
spelling |
doaj-7e4c4ff985ee448cbecdfabbc6959ad52021-03-20T04:52:54ZengElsevierNeurobiology of Disease1095-953X2006-09-01233522532Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpressionMatthew Maingay0Marina Romero-Ramos1Manolo Carta2Deniz Kirik3Corresponding author. Fax: +46 46 2223436.; Department of Experimental Medical Science, Section of Neuroscience, CNS Disease Modeling Unit, Lund University, Wallenberg Neuroscience Center, BMCA11, S-22184 Lund, SwedenDepartment of Experimental Medical Science, Section of Neuroscience, CNS Disease Modeling Unit, Lund University, Wallenberg Neuroscience Center, BMCA11, S-22184 Lund, SwedenDepartment of Experimental Medical Science, Section of Neuroscience, CNS Disease Modeling Unit, Lund University, Wallenberg Neuroscience Center, BMCA11, S-22184 Lund, SwedenDepartment of Experimental Medical Science, Section of Neuroscience, CNS Disease Modeling Unit, Lund University, Wallenberg Neuroscience Center, BMCA11, S-22184 Lund, SwedenParkinson's disease (PD) is characterized by the formation of intracytoplasmic inclusions, which contain α-synuclein (α-syn) protein. While most profound neurodegeneration is seen in the dopamine (DA) synthesizing neurons located in the ventral midbrain, it is unclear why some DA cell groups are more susceptible than others. In the midbrain, the degeneration of the substantia nigra (SN) DA neurons is severe, whereas the involvement of the ventral tegmental area (VTA) neurons is relatively spared. In the present study, we overexpressed human A53T α-syn in the VTA neurons and found that A53T toxicity did not affect their survival. There was, however, a mild functional impairment seen as altered open field locomotor activity. Overexpression of A53T in the SN, on the other hand, led to profound cell loss. These results suggest that the selective susceptibility of nigral DA neurons is at least in part associated with factor(s) involved in handling of α-syn that is not shared by the VTA neurons. Secondly, these results highlight the fact that impaired but surviving neurons can have a substantial impact on DA-dependent behavior and should therefore be considered as a critical part of animal models where novel therapeutic interventions are tested.http://www.sciencedirect.com/science/article/pii/S0969996106000933Parkinson's diseaseRecombinant adeno-associated virusα-synucleinMesolimbicCell deathStereology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matthew Maingay Marina Romero-Ramos Manolo Carta Deniz Kirik |
spellingShingle |
Matthew Maingay Marina Romero-Ramos Manolo Carta Deniz Kirik Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression Neurobiology of Disease Parkinson's disease Recombinant adeno-associated virus α-synuclein Mesolimbic Cell death Stereology |
author_facet |
Matthew Maingay Marina Romero-Ramos Manolo Carta Deniz Kirik |
author_sort |
Matthew Maingay |
title |
Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression |
title_short |
Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression |
title_full |
Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression |
title_fullStr |
Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression |
title_full_unstemmed |
Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression |
title_sort |
ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2006-09-01 |
description |
Parkinson's disease (PD) is characterized by the formation of intracytoplasmic inclusions, which contain α-synuclein (α-syn) protein. While most profound neurodegeneration is seen in the dopamine (DA) synthesizing neurons located in the ventral midbrain, it is unclear why some DA cell groups are more susceptible than others. In the midbrain, the degeneration of the substantia nigra (SN) DA neurons is severe, whereas the involvement of the ventral tegmental area (VTA) neurons is relatively spared. In the present study, we overexpressed human A53T α-syn in the VTA neurons and found that A53T toxicity did not affect their survival. There was, however, a mild functional impairment seen as altered open field locomotor activity. Overexpression of A53T in the SN, on the other hand, led to profound cell loss. These results suggest that the selective susceptibility of nigral DA neurons is at least in part associated with factor(s) involved in handling of α-syn that is not shared by the VTA neurons. Secondly, these results highlight the fact that impaired but surviving neurons can have a substantial impact on DA-dependent behavior and should therefore be considered as a critical part of animal models where novel therapeutic interventions are tested. |
topic |
Parkinson's disease Recombinant adeno-associated virus α-synuclein Mesolimbic Cell death Stereology |
url |
http://www.sciencedirect.com/science/article/pii/S0969996106000933 |
work_keys_str_mv |
AT matthewmaingay ventraltegmentalareadopamineneuronsareresistanttohumanmutantalphasynucleinoverexpression AT marinaromeroramos ventraltegmentalareadopamineneuronsareresistanttohumanmutantalphasynucleinoverexpression AT manolocarta ventraltegmentalareadopamineneuronsareresistanttohumanmutantalphasynucleinoverexpression AT denizkirik ventraltegmentalareadopamineneuronsareresistanttohumanmutantalphasynucleinoverexpression |
_version_ |
1724211921986519040 |