Double Hit

The discovery in 1982 that a badly synthesized street drug could induce Parkinsonism in young California addicts (the so-called Frozen Addicts) led to the identification of a new neurotoxin, MPTP. In subsequent animal and in vitro models, MPTP, was found to convert into a paraquat-like chemical called MPP+. This generated enormous interest in the possibility (moderately supported by subsequent epidemiological studies) that herbicides (e.g. paraquat), fungicides (e.g., maneb) and pesticides (e.g. rotenone) might cause sporadic Parkinson’s disease, perhaps by damaging the mitochondria — the nerve cell’s power source.

In a quite separate discovery in 1997, geneticists identified a mutation in a large Italian American family (the Contursi kindred). Members of this family were cursed with a very rare inherited form of Parkinsonism. The mutated gene coded for a brain protein called alpha-synuclein, which turned out to be the main ingredient in Lewy bodies, the pathological hallmark of regular sporadic PD. 

Now a study published in the prestigious scientific journal Cell by Scott Ryan et al. seeks to put these two discoveries together. It asks what happens when a neuron with the Contursi mutation is also exposed to toxins like paraquat, maneb and rotenone. Does this “double hit” reveal powerful gene-environment interactions? And does this analysis suggest ways to block one or more of PD’s disease pathways? The answers appear to be yes and yes.

Ryan and colleagues took skin cells from patients with the Contursi mutation, and reprogrammed them to become induced pluripotent stem cells (iPSCs). They then took some of these stem cells and corrected the Contursi mutation, thereby making a control cell that was genetically identical in every regard except that the mutation was missing. Then, the two populations were cajoled to become dopaminergic neurons — the nerve cells that die in PD.

The team next ran a cell culture experiment exposing these two populations of dopamine nerve cells to paraquat, maneb, and rotenone. The difference was striking. The nerve cells with the mutation were much more vulnerable to the pesticides. As Ryan says: “We observed the detrimental effects of these pesticides with short exposures to doses well below EPA-accepted levels.”

It seems that the release of free radicals in this gene environment interaction disrupts a key mitochondrial pathway — called MEF2C-PGC1alpha — that normally protects dopamine neurons. It turns out that a molecule called isoxazole can inhibit free radicals and thus protect neurons. Even better, several FDA-approved drugs contain isoxazole derivatives, so one day a repurposed drug containing isoxasole may prove beneficial against PD.

Parkinson’s is increasingly viewed as resulting from a complex interaction between genes, environment, lifestyle, age, and luck. The team’s approach suggests a promising strategy for beginning to unpack this mess. It is to be hoped that such research doesn’t imply that everyone’s PD is unique, but rather demonstrates that there are some key “dominoes” in the disease cascade, that if protected, may halt the pathology in its tracks.