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Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons.

Decressac, Mickael LU ; Mattsson, Bengt LU ; Lundblad, Martin LU ; Weikop, P and Björklund, Anders LU (2012) In Neurobiology of Disease 45(3). p.939-953
Abstract
Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound... (More)
Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alpha-Synuclein, Parkinson's disease, Adeno-associated viral vector, Motor deficit, Rat
in
Neurobiology of Disease
volume
45
issue
3
pages
939 - 953
publisher
Elsevier
external identifiers
  • wos:000300519600012
  • pmid:22182688
  • scopus:84856570373
ISSN
0969-9961
DOI
10.1016/j.nbd.2011.12.013
language
English
LU publication?
yes
id
f4fbd410-1c55-4b00-bd81-571ea4f0ce39 (old id 2273867)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22182688?dopt=Abstract
date added to LUP
2012-01-03 20:28:28
date last changed
2017-11-19 03:21:26
@article{f4fbd410-1c55-4b00-bd81-571ea4f0ce39,
  abstract     = {Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.},
  author       = {Decressac, Mickael and Mattsson, Bengt and Lundblad, Martin and Weikop, P and Björklund, Anders},
  issn         = {0969-9961},
  keyword      = {alpha-Synuclein,Parkinson's disease,Adeno-associated viral vector,Motor deficit,Rat},
  language     = {eng},
  number       = {3},
  pages        = {939--953},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons.},
  url          = {http://dx.doi.org/10.1016/j.nbd.2011.12.013},
  volume       = {45},
  year         = {2012},
}