The search for genetic mouse models of prodromal Parkinson's disease

Parkinson's disease is characterized and diagnosed by bradykinetic motor symptoms caused by the loss of dopamine neurons in the substantia nigra. The pathological and non-motor behavioral changes that occur prior to degeneration are less well characterized, although changes in gait, olfaction and cognition have been recognized in familial Parkinson's disease subjects. Gene mutations associated familial Parkinson's disease give rise to mitochondrial changes, altered energy homeostasis and intracellular trafficking deficits, and these can be modeled in transgenic mice. Here we discuss the recent finding of prodromal behavioral disturbances in a PINK1 deficient mouse that manifest prior to dopaminergic cell death and correlate to 5-HT fiber losses and mitochondrial morphological changes. We discuss the representation of the PINK1 deficient mouse and other genetic models to accurately recapitulate early Parkinson's disease. Prodromal symptoms and underlying pathology modeled in mice and cell lines from human subjects may have wide implications for earlier diagnosis. Current and emerging therapies need to be tailored to target both early cognitive and late stage motor symptoms.