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A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein-GFP.

Hansen, Christian LU ; Björklund, Tomas LU ; Petit, Géraldine LU ; Lundblad, Martin LU ; Murmu, Reena LU ; Brundin, Patrik LU and Li, Jia-Yi LU (2013) In Neurobiology of Disease 56C(April,30). p.145-155
Abstract
Compelling evidence suggests that accumulation and aggregation of alpha-synuclein (α-syn) contribute to the pathogenesis of Parkinson's disease (PD). Here, we describe a novel Bacterial Artificial Chromosome (BAC) transgenic model, in which we have expressed wild-type human α-syn fused to green fluorescent protein (GFP), under control of the mouse α-syn promoter. We observed a widespread and high expression of α-syn-GFP in multiple brain regions, including the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the ventral tegmental area, the olfactory bulb as well as in neocortical neurons. With increasing age, transgenic mice exhibited reductions in amphetamine-induced locomotor activity in the open field, impaired... (More)
Compelling evidence suggests that accumulation and aggregation of alpha-synuclein (α-syn) contribute to the pathogenesis of Parkinson's disease (PD). Here, we describe a novel Bacterial Artificial Chromosome (BAC) transgenic model, in which we have expressed wild-type human α-syn fused to green fluorescent protein (GFP), under control of the mouse α-syn promoter. We observed a widespread and high expression of α-syn-GFP in multiple brain regions, including the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the ventral tegmental area, the olfactory bulb as well as in neocortical neurons. With increasing age, transgenic mice exhibited reductions in amphetamine-induced locomotor activity in the open field, impaired rotarod performance and a reduced striatal dopamine release, as measured by amperometry. In addition, they progressively developed deficits in an odor discrimination test. Western blot analysis revealed that α-syn-GFP and phospho-α-syn levels increased in multiple brain regions, as the mice grew older. Further, we observed, by immunohistochemical staining for phospho-α-syn and in vivo by two-photon microscopy, the formation of α-syn aggregates as the mice aged. The latter illustrates that the model can be used to track α-syn aggregation in vivo. In summary, this novel BAC α-syn-GFP model mimics a unique set of aspects of PD progression combined with the possibility of tracking α-syn aggregation in neocortex of living mice. Therefore, this α-syn-GFP-mouse model can provide a powerful tool that will facilitate the study of α-syn biology and its involvement in PD pathogenesis. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neurobiology of Disease
volume
56C
issue
April,30
pages
145 - 155
publisher
Elsevier
external identifiers
  • pmid:23643841
  • scopus:84878149242
  • pmid:23643841
ISSN
0969-9961
DOI
10.1016/j.nbd.2013.04.017
language
English
LU publication?
yes
id
f3b61635-248b-4a75-805b-4a1e85415849 (old id 3804875)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23643841?dopt=Abstract
date added to LUP
2016-04-04 07:29:05
date last changed
2020-10-07 04:30:53
@article{f3b61635-248b-4a75-805b-4a1e85415849,
  abstract     = {Compelling evidence suggests that accumulation and aggregation of alpha-synuclein (α-syn) contribute to the pathogenesis of Parkinson's disease (PD). Here, we describe a novel Bacterial Artificial Chromosome (BAC) transgenic model, in which we have expressed wild-type human α-syn fused to green fluorescent protein (GFP), under control of the mouse α-syn promoter. We observed a widespread and high expression of α-syn-GFP in multiple brain regions, including the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the ventral tegmental area, the olfactory bulb as well as in neocortical neurons. With increasing age, transgenic mice exhibited reductions in amphetamine-induced locomotor activity in the open field, impaired rotarod performance and a reduced striatal dopamine release, as measured by amperometry. In addition, they progressively developed deficits in an odor discrimination test. Western blot analysis revealed that α-syn-GFP and phospho-α-syn levels increased in multiple brain regions, as the mice grew older. Further, we observed, by immunohistochemical staining for phospho-α-syn and in vivo by two-photon microscopy, the formation of α-syn aggregates as the mice aged. The latter illustrates that the model can be used to track α-syn aggregation in vivo. In summary, this novel BAC α-syn-GFP model mimics a unique set of aspects of PD progression combined with the possibility of tracking α-syn aggregation in neocortex of living mice. Therefore, this α-syn-GFP-mouse model can provide a powerful tool that will facilitate the study of α-syn biology and its involvement in PD pathogenesis.},
  author       = {Hansen, Christian and Björklund, Tomas and Petit, Géraldine and Lundblad, Martin and Murmu, Reena and Brundin, Patrik and Li, Jia-Yi},
  issn         = {0969-9961},
  language     = {eng},
  number       = {April,30},
  pages        = {145--155},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein-GFP.},
  url          = {http://dx.doi.org/10.1016/j.nbd.2013.04.017},
  doi          = {10.1016/j.nbd.2013.04.017},
  volume       = {56C},
  year         = {2013},
}