Genetic Models of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative movement disorder. To understand the pathomechanisms and to develop new drugs and therapies for PD, it is important to have animal models that recapitulate the slow progression and symptoms of the disease. The generation of genetic animal models of genes responsible for autosomal dominant but also autosomal recessive forms of PD has indeed accelerated our understanding of these pathomechanisms. To model the effect of dominant mutant alleles, transgenic mice were produced that express mutation-bearing proteins in neurons. To model loss-of-function alleles, knockout mice were generated and studied. However, none of these models recapitulate PD disease as it occurs in PD patients. The latest mouse genetic technology may offer, at least in part, a relief for these challenges through the timed control of protein expression or gene knockout. Both can be achieved by the use of the Tamoxifen inducible CreERT² gene switch that enables the inducible activation of transgene expression or inducible gene knockout. Thereby the CreER^T2 system can be used to generate genetic models of gain-of-function (dominant) disease-associated alleles by the regulated expression of mutant coding regions as well as to model loss-of-function (recessive) disease-associated alleles by inducible gene knockout. In this chapter, we cover the design of such Tamoxifen inducible transgene constructs and the use of premade conditional knockout alleles generated by large-scale mutagenesis projects. Furthermore, we provide an overview of the available brain-specific CreER^T2 mouse lines, notes on the control groups for inducible knockout experiments and a protocol for Tamoxifen administration.