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

Jessie L. St Martin, Jochen Klucken, Tiago F. Outeiro, Paul Nguyen, Christine Keller-McGandy, Ippolita Cantuti-Castelvetri, Tom N. Grammatopoulos, David G. Standaert, Bradley T. Hyman, Pamela J. McLean

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Several transgenic mouse lines with altered α-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 α-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 α-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 α-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 α-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 α-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.

Original languageEnglish (US)
Pages (from-to)1449-1457
Number of pages9
JournalJournal of neurochemistry
Volume100
Issue number6
DOIs
StatePublished - Mar 1 2007

Keywords

  • Adeno-associated virus
  • Heat shock proteins
  • Laser capture microdissection
  • Parkinson's disease
  • Substantia nigra
  • α-synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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  • Cite this

    St Martin, J. L., Klucken, J., Outeiro, T. F., Nguyen, P., Keller-McGandy, C., Cantuti-Castelvetri, I., Grammatopoulos, T. N., Standaert, D. G., Hyman, B. T., & McLean, P. J. (2007). Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. Journal of neurochemistry, 100(6), 1449-1457. https://doi.org/10.1111/j.1471-4159.2006.04310.x