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

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.