Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra.

Academic Article

Abstract

  • Several transgenic mouse lines with altered alpha-synuclein expression have been developed that show a variety of Parkinson's disease-like symptoms without specific loss of dopaminergic neurons. Targeted over-expression of human alpha-synuclein using viral-vector mediated gene delivery into the substantia nigra of rats and non-human primates leads to dopaminergic cell loss and the formation of alpha-synuclein aggregates reminiscent of Lewy bodies. In the context of these recent findings, we used adeno-associated virus (AAV) to over-express wild type human alpha-synuclein in the substantia nigra of mice. We hypothesized that this over-expression would recapitulate pathological hallmarks of Parkinson's disease, creating a mouse model to further characterize the disease pathogenesis. Recombinant AAV expressing alpha-synuclein was stereotaxically injected into the substantia nigra of mice, leading to a 25% reduction of dopaminergic neurons after 24 weeks of transduction. Furthermore, examination of mRNA levels of stress-related proteins using laser capture microdissection and quantitative PCR revealed a positive correlation of Hsp27 expression with the extent of viral transduction at 4 weeks and a positive correlation of Hsp40, Hsp70 and caspase 9 with the extent of viral transduction at 24 weeks. Taken together, our findings suggest that targeted over-expression of alpha-synuclein can induce pathology at the gross anatomical and molecular level in the substantia nigra, providing a mouse model in which upstream changes in Parkinson's disease pathogenesis can be further elucidated.
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    Keywords

  • Animals, Cell Death, Dependovirus, Dopamine, Green Fluorescent Proteins, Humans, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Molecular Chaperones, Neurons, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Substantia Nigra, Time Factors, Tyrosine 3-Monooxygenase, Up-Regulation, alpha-Synuclein
  • Digital Object Identifier (doi)

    Author List

  • St Martin JL; Klucken J; Outeiro TF; Nguyen P; Keller-McGandy C; Cantuti-Castelvetri I; Grammatopoulos TN; Standaert DG; Hyman BT; McLean PJ
  • Start Page

  • 1449
  • End Page

  • 1457
  • Volume

  • 100
  • Issue

  • 6