Why does it take 60 years for Parkinson’s symptoms to emerge?

One of the outstanding questions in Parkinson’s research is what enables the nerve cells in the region of the brain affected in Parkinson’s (i.e. substantia nigra) to tolerate the insults of the disease for over 60 years (in late onset Parkinson’s) before symptoms emerge? Conversely, in early onset Parkinson’s (symptoms emerge before 60) why is this tolerance missing?

I listened to a talk given by Prof Ole Isacson (Harvard) at the OPDC where he discussed a fascinating possibility to explain this puzzle. I will try to explain what I understood of his reasoning (the analogy is my way to understand the idea):

Imagine some annoying person is tapping you on the shoulder. Initially it is very gentle so you barely notice it. But the tapping becomes steadily harder and eventually begins to hurt. At a certain point you lose patience, "STOP IT or I'm leaving!"

The thing that annoys cells in your body is highly reactive chemicals called reactive oxidative species, which are by-products of energy production in the cell. These chemicals tap the cell on the shoulder but they are tolerated because the cell normally either neutralises the chemical before cellular damage can occur or repairs the damage (the cell can shrug off the shoulder tapper). However, as the cell ages, natural damage accumulates (repair isn't perfect) and the tolerance of the cell to damage is overwhelmed. Eventually the cell loses patience ("STOP IT or I'm leaving!") and presses the self-destruct button and dies (in a process called apoptosis or programmed cell death).

Now imagine your shoulder has been very active doing exercise and is sore to the touch. But the tapping starts again. Your patience wears very thin a lot quicker this time.

This is what happens in nerve cells that die in Parkinson's: these cells are very active and need lots of energy so they generate lots of reactive chemicals and are prone to more damage; the shoulder is sensitive to even the lightest touch. Add to this the extra reactive chemicals generated as a result of Parkinson's gene mutations and these high energy dopamine nerve cells press the self-destruct button sooner and are preferentially lost.

In other words, the threshold for triggering self-destruction of these cells gradually declines with age, which may exaggerate the affect of Parkinson's associated mutations in later stages of life (initially the Parkinson's affect is small because it is well tolerated but increases as tolerance declines). This provides one possible explanation why in most cases Parkinson's emerges after 60 years of life.

This raises the question, what make cells in early onset Parkinson’s (I was diagnosed age 33) especially intolerant of this natural wear and tear of the cell? What is it about the changes in my DNA that makes cell death occur earlier?

Thinking of new avenues of treatment: how can we boost this tolerance so we can push back onset of symptoms by another 60 years?

Prof Isacson’s idea demonstrates what all good ideas in science do: raise more questions!