In vivo models of Parkinson’s disease – Mammalian models

Genetic models

Engrailed mutant mouse

Genetic analyses have identified several gene mutations in familial forms of Parkinson’s disease (PD). However, in most case the disease is sporadic/idiopathic and is complexed by the interplay between genetic risk factors and environmental factors. Results of large genetic evaluations have suggested that a polymorphism in the human gene called engrailed 1 (En1) may be associated with increased susceptibility to develop PD.

Mesencephalic dopaminergic neurons are determined during development by the sequential expression of growth factors as well as transcription factors commonly referred to as homeoproteins.

En1 is a homeogene that, together with pentraxin-related gene 3 (Pitx3) and engrailed 2 (En2) plays an important function in late stages of dopaminergic cell development and may be involved in neuron survival. En1 intervenes at an earlier point than En2 in the development of dopaminergic neurons. In the adult mouse brain En1 is predominantly expressed in the tectum, and in dopaminergic cells in the SN and VTA.

The consequences of the partial or complete deletion of En1 seems to depend on genetic factors outside of the En1 locus and are distinct in different mouse strains. Homozygous C57BL/6 En1-/- mice are viable and heterozygous C57BL/6 En1-/+ mice show no nigrostriatal neurodegeneration, or require the deletion of the En2 gene. Conversely homozygous mice on a 129/Sv, C57BL/6×129/Sv, and Swiss/OF1 background die at birth.

The heterozygous Swiss/OF1 En1-/+, the Engrailed mutant mouse, which displays evidence of dopaminergic degeneration, is an important model to study the pathogenesis of PD.