Browsing by Author "Pätsi, Sauli"

Parkinson's disease is a neurodegenerative disease which is characterized by progressive loss of dopaminergic neurons in the substantia nigra and formation of intracellular Lewy bodies. α-synuclein is an essential part of Lewy bodies. In addition, mutations in the α-synuclein gene have been found to cause rare familial forms of Parkinson's disease. Animal models of Parkinson's disease are created by neurotoxins, transgenic animals and viral vectors. Transgenic animal models and viral vector models seem to reflect the pathology of Parkinson's disease better than the traditional neurotoxin models. In the transgenic animal models, the transgene and the promoter used in the expression of the transgene guide the pathology and motor dysfunctions that the animal model exhibits. In the viral vector models, it is important to use a suitable animal strain and a correct viral serotype in order to express the transgene sufficiently enough in the laboratory animals. The aim of the study was to investigate the ability of adeno-associated viral vector (AAV1-vector) to transfect WT- or A53T-α-synuclein gene into the striatum or the substantia nigra, and the effects of their overexpression on motor functions and concentrations of striatal dopamine and its metabolites in mice. In addition, the effect of a prolyl endopeptidase (PREP) inhibitor on the overexpression of A53T-α-synuclein in the mouse nigrostriatal pathway was studied, as PREP has been found to stimulate the aggregation of α-synuclein and therefore perhaps to increase neurotoxicity of α-synuclein. There were no statistically significant differences between the groups in the motor function tests (locomotor activity, rotarod and balance beam walk). Green fluorescent protein immunostaining showed that the GFP gene was weakly transfected into the striatum by the AAV1-vector, and no overexpression was observed. There were only minor differences in the striatal concentrations of dopamine and its metabolites. Finally, PREP-activity measurements showed that PREP-inhibitor (KYP-2047) treatment had poorly reduced PREP-activity. In this study, the viral vectors did not induce the overexpression of α-synuclein, although previously AAV2- and AAV6-vectors have been efficient in mice and rats. High PREP-activities that were found in most of the samples probably resulted from failed installations of mini-pumps that delivered the PREP-inhibitor. While in this study the viral vectors were not a successful attempt in the creation of an animal model of Parkinson's disease, they are an important method to model Parkinson's disease in the future.