Abstract
Pathological modification of α-synuclein is believed to be an important event in pathogenesis of Parkinson’s disease and several other neurodegenerative diseases. In normal cells this protein has been linked to many intracellular processes and pathways. However, neither normal function of α-synuclein in neuronal and certain other types of cells nor its exact role in the disease pathogenesis is well understood, which is largely due to limitations of animal models used for studying this protein. We produced and validated several novel mouse lines for manipulating expression of the endogenous Snca gene coding for α-synuclein. These include a line for conditional Cre-recombinase-driven inactivation of the gene; a line for conditional Flp-driven restoration of a neo-cassete-blocked α-synuclein expression; a new line with a “clean” constituent knockout of the gene as well as a line carrying this knockout locus and Rosa26-stop-lacZ reporter locus linked at the same mouse chromosome 6. Altogether these lines represent a set of new useful tools for studies of α-synuclein normal function and the role of this protein in disease pathogenesis.
Highlights
Pathological modification of α-synuclein is believed to be an important event in pathogenesis of Parkinson’s disease and several other neurodegenerative diseases
Certain structural modifications or increased expression of this protein have been associated with the development of early onset forms of PD4–9, whereas polymorphisms in the encoding locus, SNCA, have been found to affect the risk of the development of Parkinson’s disease (PD) and certain other synucleinopathies[10,11,12,13,14]
It is feasible that substantial changes in α -synuclein metabolism lead to the development of aggressive forms of the disease, while more subtle modifications can be efficiently compensated for a long time
Summary
Pathological modification of α-synuclein is believed to be an important event in pathogenesis of Parkinson’s disease and several other neurodegenerative diseases. Depletion of α -synuclein in adult rat substantia nigra by injection of siRNA-encoding AAV viruses caused a rapid development of substantially more severe neuronal dysfunction than observed in any of the previously produced animal lines with constituent inactivation of the Snca gene[35].
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