BackgroundAlpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra.ResultsWe noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants.ConclusionsIn conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7.

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Parkinson's disease is a common neurodegenerative disorder whose aetiology is not yet fully understood. In the past ten years, the discovery of genes linked to hereditary forms of the disease has impelled the development of animal models. These should lead to the identification of novel pathways that provide insight into the functionality of the proteins involved and the pathogenesis of the sporadic forms of the disease. In particular, loss-of-function mutations in the parkin and PINK1 (phosphatase and tensin homolog (PTEN)-induced kinase 1) genes account for most of the cases of familial autosomal recessive parkinsonism. Both parkin and PINK1 knockout rodent models are now available, which display an overall mild phenotype consisting of a mitochondrial dysfunction together with changes in dopamine metabolism and oxidative stress. However, up till now these models fail to reproduce the main hallmarks of Parkinson's disease: the dopaminergic cell loss in the substantia nigra and the presence of cytoplasmic inclusions, named Lewy bodies, in the remaining dopaminergic neurons. We here review the most important knockout and knockdown rodent models generated so far for these two recessive Parkinson's disease-causing genes. We critically feature their main characteristics and their impact on the research field, and propose some future directions for the study and modelling of the loss of function of parkin and PINK1 in rodents.

BackgroundAlpha-synuclein is a key protein in the pathogenesis of Parkinson’s disease. Mutations in the parkin gene are the most common cause of early-onset autosomal recessive Parkinson’s disease, probably through a loss-of-function mechanism. However, the molecular mechanism by which loss of parkin function leads to the development of the disease and the role of alpha-synuclein in parkin-associated Parkinson’s disease is still not elucidated. Conflicting results were reported about the effect of the absence of parkin on alpha-synuclein-mediated neurotoxicity using a transgenic approach. In this study, we investigated the effect of loss of parkin on alpha-synuclein neuropathology and toxicity in adult rodent brain using viral vectors. Therefore, we overexpressed human wild type alpha-synuclein in the substantia nigra of parkin knockout and wild type mice using two different doses of recombinant adeno-associated viral vectors.ResultsNo difference was observed in nigral dopaminergic cell loss between the parkin knockout mice and wild type mice up to 16 weeks after viral vector injection. However, the level of alpha-synuclein phosphorylated at serine residue 129 in the substantia nigra was significantly increased in the parkin knockout mice compared to the wild type mice while the total expression level of alpha-synuclein was similar in both groups. The increased alpha-synuclein phosphorylation was confirmed in a parkin knockdown cell line.ConclusionsThese findings support a functional relationship between parkin and alpha-synuclein phosphorylation in rodent brain.