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Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathology.

Ulusoy, Ayse LU ; Febbraro, Fabia LU ; Jensen, Poul H; Kirik, Deniz LU and Romero-Ramos, Marina LU (2010) In European Journal of Neuroscience 32(3). p.409-422
Abstract
Lewy bodies, which are a pathological hallmark of Parkinson's disease, contain insoluble polymers of alpha-synuclein (alphasyn). Among the different modifications that can promote the formation of toxic alphasyn species, C-terminal truncation is among the most abundant alterations in patients with Parkinson's disease. In vitro, C-terminal truncated alphasyn aggregates faster and sub-stoichiometric amounts of C-terminal truncated alphasyn promote aggregation of the full-length alphasyn (alphasynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of alphasyn-induced pathology by the presence of truncated alphasyn, we used recombinant adeno-associated virus to express either alphasynFL or a C-terminal truncated... (More)
Lewy bodies, which are a pathological hallmark of Parkinson's disease, contain insoluble polymers of alpha-synuclein (alphasyn). Among the different modifications that can promote the formation of toxic alphasyn species, C-terminal truncation is among the most abundant alterations in patients with Parkinson's disease. In vitro, C-terminal truncated alphasyn aggregates faster and sub-stoichiometric amounts of C-terminal truncated alphasyn promote aggregation of the full-length alphasyn (alphasynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of alphasyn-induced pathology by the presence of truncated alphasyn, we used recombinant adeno-associated virus to express either alphasynFL or a C-terminal truncated alphasyn (1-110) in rats. We adjusted the recombinant adeno-associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of alphasyn were co-expressed at these pre-determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C-terminal truncated alphasyn (1-110) but only alphasynFL, we demonstrated that the co-expressed truncated protein promoted the progressive accumulation of alphasynFL and formation of larger pathological accumulations. Moreover, in the co-expression group, three of the eight animals showed apomorphine-induced turning, suggesting prominent post-synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C-terminal truncated alphasyn can interact with and exacerbate the formation of pathological accumulations containing alphasynFL in vivo. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Journal of Neuroscience
volume
32
issue
3
pages
409 - 422
publisher
Wiley-Blackwell
external identifiers
  • wos:000280631600011
  • pmid:20704592
  • scopus:77955141273
ISSN
1460-9568
DOI
10.1111/j.1460-9568.2010.07284.x
language
English
LU publication?
yes
id
e1da01ff-e8a2-4148-bc5d-698d33317fa3 (old id 1665302)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20704592?dopt=Abstract
date added to LUP
2010-09-03 10:43:59
date last changed
2018-07-15 04:17:35
@article{e1da01ff-e8a2-4148-bc5d-698d33317fa3,
  abstract     = {Lewy bodies, which are a pathological hallmark of Parkinson's disease, contain insoluble polymers of alpha-synuclein (alphasyn). Among the different modifications that can promote the formation of toxic alphasyn species, C-terminal truncation is among the most abundant alterations in patients with Parkinson's disease. In vitro, C-terminal truncated alphasyn aggregates faster and sub-stoichiometric amounts of C-terminal truncated alphasyn promote aggregation of the full-length alphasyn (alphasynFL) and induce neuronal toxicity. To address in vivo the putative stimulation of alphasyn-induced pathology by the presence of truncated alphasyn, we used recombinant adeno-associated virus to express either alphasynFL or a C-terminal truncated alphasyn (1-110) in rats. We adjusted the recombinant adeno-associated virus vector concentrations so that either protein alone led to only mild to moderate axonal pathology in the terminals of nigrostriatal dopamine neurons without frank cell loss. When these two forms of alphasyn were co-expressed at these pre-determined levels, it resulted in a more aggressive pathology in fiber terminals as well as dopaminergic cell loss in the substantia nigra. Using an antibody that did not detect the C-terminal truncated alphasyn (1-110) but only alphasynFL, we demonstrated that the co-expressed truncated protein promoted the progressive accumulation of alphasynFL and formation of larger pathological accumulations. Moreover, in the co-expression group, three of the eight animals showed apomorphine-induced turning, suggesting prominent post-synaptic alterations due to impairments in the dopamine release, whereas the mild pathology induced by either form alone did not cause motor abnormalities. Taken together these data suggest that C-terminal truncated alphasyn can interact with and exacerbate the formation of pathological accumulations containing alphasynFL in vivo.},
  author       = {Ulusoy, Ayse and Febbraro, Fabia and Jensen, Poul H and Kirik, Deniz and Romero-Ramos, Marina},
  issn         = {1460-9568},
  language     = {eng},
  number       = {3},
  pages        = {409--422},
  publisher    = {Wiley-Blackwell},
  series       = {European Journal of Neuroscience},
  title        = {Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathology.},
  url          = {http://dx.doi.org/10.1111/j.1460-9568.2010.07284.x},
  volume       = {32},
  year         = {2010},
}