Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression.

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Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression. / Maingay, Matthew; Romero-Ramos, Marina; Carta, Manolo; Kirik, Deniz.

In: Neurobiology of Disease, Vol. 23, No. 3, 2006, p. 522-532.

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Maingay, Matthew ; Romero-Ramos, Marina ; Carta, Manolo ; Kirik, Deniz. / Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression. In: Neurobiology of Disease. 2006 ; Vol. 23, No. 3. pp. 522-532.

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TY - JOUR

T1 - Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression.

AU - Maingay, Matthew

AU - Romero-Ramos, Marina

AU - Carta, Manolo

AU - Kirik, Deniz

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

KW - Cell death

KW - Mesolimbic

KW - α-synuclein

KW - Recombinant adeno-associated virus

KW - Parkinson's disease

KW - Stereology

KW - Tyrosine hydroxylase

KW - Open field activity

U2 - 10.1016/j.nbd.2006.04.007

DO - 10.1016/j.nbd.2006.04.007

M3 - Article

VL - 23

SP - 522

EP - 532

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 3

ER -