If genetics and toxins only account for a small fraction of Parkinson’s cases, then what causes the rest?

Short answer:  We don’t know.

Longer answer:  Most cases of Parkinson’s disease are called ‘idiopathic’, because this sounds better than ‘we have no idea what caused your disease’.  I have found that this uncertainty about the cause of disease makes patients, clinicians, and scientists rather uneasy.  Fair enough, since it may reflect our ignorance concerning the biological basis of Parkinson’s disease.

But other interpretations are possible.  One is that most cases of Parkinson’s may arise from some interplay between genes and environment, which would of course be difficult to identify.  I have heard quotes similar to the following several times, including from Michael J. Fox:  “Genetics loads the gun, but the environment pulls the trigger”.  In other words, many people may have some genetic predisposition, but only some develop Parkinson’s, due to some unidentified factor in the environment.  This theory has the virtue of making sense; after all, other than genetics and the environment (nature and nurture), what else is there?

The problem is, to my knowledge, there is no strong evidence to support this concept; it remains a hypothesis.  I would also like to suggest one other possible cause for Parkinson’s:  bad luck.  Not bad luck in terms of having bad genes or being exposed to some nasty environmental factor, but rather a random event.  This concept makes many people profoundly uneasy.  It is best accepted and understood in cancer.  Every day, the billions of nucleotides in your DNA are copied during cell division millions of times, and inevitably there are random errors.  Most of the time, these are corrected by quality control mechanisms in the cell, or even if they are not, they are usually relatively harmless.  But every once in a while, a cell goes haywire; if it starts to replicate out of control, and is not eliminated by the immune system, then cancer can result.  All because of one random error in your 4 billion DNA nucleotides in your trillions of cells.  Bad luck.

Neurodegenerative diseases are rather different, but protein misfolding may be a somewhat analogous process in that a random event can get propagated and amplified over time.  One protein misfolds, and that causes more proteins to misfold as a result; the process is ‘autocatalytic’.  [In Parkinson’s, the misfolding protein would be alpha-synuclein.]  Normally, these protein aggregates are efficiently cleared by the cell, but in some cases, the misfolding may overwhelm the cell’s defenses.  Eventually, the misfolded proteins get out of the cell where they normally would get cleared out by other processes, but once in a while they are taken up by another cell, where the misfolding continues to propagate.  Bad luck.

But we just don’t know.