Figure 1. Modeling the progressive neurodegeneration of Parkinson’s disease.

A) PD pathogenesis occurs years before onset of symptoms and typical diagnosis. Compensatory processes can mask or limit symptoms until death of dopaminergic neurons is widespread. While some compensations such as upregulation of postsynaptic receptors have been identified, they are not well understood and may contribute to the disease process itself. B) Like humans with PD, MitoPark mice exhibit a decline in nigrostriatal function that is adult onset, steadily progressive, and ultimately terminal. Toxin models can mimic neuronal death and can be titrated for effect, but are notoriously variable and produce degeneration on a rapid time scale that does not mimic PD. Models based on human genetic studies unfortunately have until now shown only mild behavioral and neurodegenerative phenotypes.