The etiology of Parkinson's disease with emphasis on the MPTP story

During the last decade there has been a tremendous resurgence of interest in the etiology of Parkinson's disease (PD), despite the fact that there is, as yet, no direct evidence as to its cause. Nonetheless, most of those working in the field remain undaunted, proceeding full steam ahead to take advantage of the clues and leads that now seem so plentiful. While much of the original stimulus for this "etiological renaissance" stems from the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a simple pyridine moiety that is selectively toxic to the dopaminergic neurons of the substantia nigra, the research on the cause of PD has taken on a life of its own. Avenues of investigation range from the newly evolving field of molecular epidemiology to neurochemical studies of nitric oxide, gas that is also a neurotransmitter, and perhaps a killer of nerve cells.

In this article, some of the history that has gotten us to this point will be reviewed, with a particular emphasis on the MPTP story. Where appropriate, future research directions will be sketched out. At the same time however, one of the broader purposes of this article is to perform what might be called a "reality check" on current research, by providing a gentle reminder of the many phenomena that must be explained by any etiologic hypothesis which is to be seriously considered.

Background and history.

Interest in the cause of PD has waxed and waned throughout this century. One of the peaks almost certainly occurred with the advent of postencephalitic parkinsonism, which enhanced interest in the syndrome not only because of its widespread appearance after the great pandemic of 1918 to 1920, but also because it appeared to hold clues to the cause of the disease, since the syndrome so clearly followed an encephalitic illness. While it is now clear that postencephalitic …