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

Maingay, Matthew LU ; Romero-Ramos, Marina LU ; Carta, Manolo LU and Kirik, Deniz LU (2006) In Neurobiology of Disease 23(3). p.522-532
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell death, Mesolimbic, α-synuclein, Recombinant adeno-associated virus, Parkinson's disease, Stereology, Tyrosine hydroxylase, Open field activity
in
Neurobiology of Disease
volume
23
issue
3
pages
522 - 532
publisher
Elsevier
external identifiers
  • pmid:16806952
  • wos:000240306000004
  • scopus:33747441863
ISSN
0969-9961
DOI
10.1016/j.nbd.2006.04.007
language
English
LU publication?
yes
id
8eceda0c-94e8-49c4-ae59-d6ec81641b41 (old id 158043)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16806952&dopt=Abstract
date added to LUP
2016-04-01 12:32:27
date last changed
2020-01-12 10:01:13
@article{8eceda0c-94e8-49c4-ae59-d6ec81641b41,
  abstract     = {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.},
  author       = {Maingay, Matthew and Romero-Ramos, Marina and Carta, Manolo and Kirik, Deniz},
  issn         = {0969-9961},
  language     = {eng},
  number       = {3},
  pages        = {522--532},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression.},
  url          = {http://dx.doi.org/10.1016/j.nbd.2006.04.007},
  doi          = {10.1016/j.nbd.2006.04.007},
  volume       = {23},
  year         = {2006},
}