Abstract:
In order to study the molecular pathways of Parkinson’s disease (PD)
and to develop novel therapeutic strategies, scientific investigators rely on animal
models. The identification of PD-associated genes has led to the development of
genetic PD models as an alternative to toxin-based models. Viral vector-mediated
loco-regional gene delivery provides an attractive way to express transgenes in the
central nervous system. Several vector systems based on various viruses have
been developed. In this chapter, we give an overview of the different viral
vector systems used for targeting the CNS. Further, we describe the different viral
vector-based PD models currently available based on overexpression strategies for
autosomal dominant genes such as a-synuclein and LRRK2, and knockout or
knockdown strategies for autosomal recessive genes, such as parkin, DJ-1, and
PINK1. Models based on overexpression of a-synuclein are the most prevalent and
extensively studied, and therefore the main focus of this chapter. Many efforts
have been made to increase the expression levels of a-synuclein in the dopami-
nergic neurons. The best a-synuclein models currently available have been
developed from a combined approach using newer AAV serotypes and optimized
vector constructs, production, and purification methods. These third-generation
a-synuclein models show improved face and predictive validity, and therefore
offer the possibility to reliably test novel therapeutics.
