5 reasons why Engrailed-1 mice are a great model to study Parkinson’s disease and test new therapies

The key features of Parkinson’s disease (PD) include slow progressive retrograde degeneration of substantia nigra dopaminergic neurons, motor and non-motor deficits, and protein aggregation. Though, none of the existing rodent PD models – both toxin-based and genetic – demonstrate all (or even most of) those traits. A new genetic mouse model was recently found to recapitulate several key aspects of PD (1). It involves heterozygous deletion of the gene encoding Engrailed-1 – a transcription factor important development and maintenance of midbrain dopaminergic neurons. The mechanisms of Engrailed-1 action include regulation of mitochondrial function and autophagy. In clinical studies, polymorphisms in Engrailed-1 have been suggested to be linked to increased PD risk.

Here are five most important traits of the Engrailed-1 heterozygous knock-out (En1 +/-) mice that make them an excellent mouse model for testing new potential disease-modifying PD therapies:

1. Slow progressive neurodegeneration

Most of the PD mouse models fail to demonstrate the slow retrograde degeneration of nigral dopaminergic neurons, a key pathological feature of PD. At birth, En1 +/- mice exhibit normal numbers of nigral dopamine neurons. At 8 days of age the first subtle degenerative changes appear in nigrostriatal axons. By 4 weeks, the striatal dopamine depletion becomes apparent. Further on, the slow, progressive degeneration of the nigral dopaminergic neurons is observed between 8 and 24 weeks, that is later followed by the behavioral dysfunction (seen first at 16 weeks). Moreover, reductions in striatal dopamine levels are associated with marked reductions in regional dopamine release and uptake in the dorsal striatum. In ongoing studies at Dr. Patrik Brundin’s lab at Van Andel Research Institute, Grand Rapids, MI, some of those changes were reversed by treatment with a new drug (under preclinical development) that enhances mitochondrial function.

2. Substantia nigra affected, but ventral tegmental area spared

In PD neurodegeneration is apparent in many brain regions, though, the death of dopaminergic neurons in the substantia nigra pars compacta is strongly linked to motor symptoms in the patients. In the En1 +/- mice, substantia nigra dopamine neurons gradually diminish in number from 8 to 48 weeks, while the adjacent ventral tegmental area dopaminergic neurons remain relatively spared (2).

3. Dying-back axonopathy

Recent post-mortem brain analyses suggests that the PD process is initiated at the level of the dopamine terminals in the striatum and that the neuronal death, i.e. loss of cell bodies in the substantia nigra, occurs months or years later. In En1 +/- mice, dopaminergic axonal changes (e.g. swollen terminal structures filled with abnormal autophagic vacuoles) are apparent several weeks before the cell bodies of nigral dopamine neurons die.

4. Autophagy

Altered autophagy appears to play a key role in PD. In the En1 +/- mice, up-regulation of the mTOR signaling (key regulator of autophagy) is apparent in nigral dopamine neurons. T his finding, together with abnormal autophagic vacuoles in the nigral terminals, suggests disturbed autophagy, akin to what is reported to occur in PD.

5. Repertoire of behavioral changes 

In many genetic models of PD, neurodegenerative changes are not linked to behavioral changes. However, the En1 +/- mice exhibit behavioral deficits, both motor and non-motor phenotypes. The mice also perform poorly in social interactions (2).

– Zuzanna Kurowska

References

1. Brundin P et al., (2015) Neurobiology Disease 73:70-82

2. Sonnier L et al., (2007) Journal of Neuroscience 27(5):1063-71