Why do nerve cells die in Parkinson's?

Parkinson’s disease is caused primarily by loss of dopamergic (dopamine producing) nerve cells in a structure of the brain called the substantia nigra. This results in reduced levels of dopamine and inefficient activation of networks of nerve cells that initiate and control movement. Why do dopamergic nerve cells die?

Analogy

Imagine a party is underway and all the components of the cell are happily dancing to the music. Mitochondria, who are waiters at the party, are handing out ATP energy drinks to keep the guests going. The organiser of the party, DNA, is pleased with how the party is progressing and plays another record. The cellular components continue to dance. Then something goes wrong. Mitochondria start serving drinks spiked with reactive oxidative species and the guests gradually get drunk; they no longer dance in a coordinated way. One group of guests at the party, alpha-synuclein, gather together in big clumps on the dance floor and prevent other guests from moving freely. Eventually DNA becomes intoxicated and plays increasingly erratic music; the guests dance wildly. This behaviour just won’t do! The apoptosis police are called into action and they start to shut down the party; guests are stopped from dancing and are arrested; DNA breaks down and the music fades. The cell dies.

What is happening in cells?

Dopamergic nerves cells in the substantia nigra consume lots of energy. As a result they require the power plants of the cell, mitochondria, to work hard replacing the lost energy. A by-product of energy production are “oxidative reactive species”, which are highly reactive chemicals that could damage DNA and proteins. Therefore, dopamergic nerve cells are said to be under “oxidative stress” because there are lots of oxidative reactive species in these cells; if anything went wrong they are more susceptible to damage.

All cells have a fail-safe mechanism called “apoptosis” (or programmed cell death), which has evolved to prevent malfunctioning cells from accumulating damage to DNA and proteins that could potentially lead to uncontrolled cell division and other toxic affects. Once damage is detected and apoptosis is triggered, a cascade of events takes place within the cell to cause its self-destruction.

It has been shown in Parkinson’s disease there are two main causes identified so far that increase oxidative stress, damage cells, trigger apoptosis and ultimately results in loss of nerve cells. Inherited mutations or environmental agents that disrupt the function or physical structure of mitochondria can increase oxidative stress. Similarly, accumulation of the protein alpha-synuclein in Lewy bodies, a common feature of nerve cells in Parkinson’s, can lead to increased levels of oxidative stress and cellular damage.