Parkinson’s disease affects around one million people in the US and between seven and ten million worldwide.

In people with Parkinson’s disease, the neurons in the brain that produce dopamine die off. Dopamine is a neurotransmitter, a chemical that helps send messages in the brain. It is involved in many functions such as movement, reward, memory, sleep regulation, nausea, motivation and arousal and many more. Thus a reduction in dopamine can affect a person in many ways.

Substantia Nigra

People with Parkinson’s disease lose cells in the substantia nigra. The substantia nigra is part of the midbrain and is the area of the brain that produces a large amount of dopamine. It is also an area involved in the movement. But the dopamine that this area produces moves throughout the brain and is used by areas involved in learning and emotion.

One treatment for Parkinson’s disease is medication that contains dopamine, to replace or enhance the low or missing levels of dopamine in the brain. But researchers have been working to understand the processes by which neurons in the brains of people with Parkinson’s disease die. To understand some of this research, it is important to remember some of the structures of cells throughout the body and how cells create proteins. We introduced cells in a previous post called Understanding Cells. Cells are composed of a nucleus and smaller structures called organelles. The nucleus and three types of organelles are important in the creation of proteins.

Nucleus

The nucleus contains the blueprints for protein creation in the genetic code.

There are rare forms of Parkinson’s disease in which just one faulty copy of a gene can cause it. The Alpha-synuclein (SNCA) and the LRRK2 are examples. Two faulty genes (autosomal recessive)- PARK7, PINK1 or PRKN– can cause Parkinson’s disease. There are also genes, like altered GBA, that increase the risk of Parkinson’s in some families.

Organelles

Creation of proteins occurs in an organelle called the ribosome. If there is a faulty genetic code or if there is a mistake in the creation of the protein in the ribosome—like a problem in the way it is folded– there is a process in place to get rid of the damaged protein. Molecules in the cell, called chaperones, watch out for damaged proteins. If a chaperone finds one, it moves the damaged protein to the lysosomes. There, it is broken down and any useful parts are recycled.

Research by Cuervo and her associates have clarified problems with this particular process called CMA (for chaperone-mediated autophagy). Sometimes this process is blocked. In Parkinson’s disease, when the process is stopped or reduced, proteins are not being broken down. They accumulate in clumps.

Mitochondria have the primary role of energy productions. They are also involved in the use of calcium and also in generating oxides or free radicals but also in utilizing anti-oxidants to detoxify them. The mitochondria maintain a balance within the cells.

Research described in Science in 2017 by Burbulla and her associates explains some of what happens over time in the neurons leading to Parkinson’s disease.  Their research has tracked the development of disease-producing biochemical changes that start with the mitochondria. An imbalance occurs with the number of free radicals and anti-oxidants. Oxidized dopamine accumulates in the neurons leading to a reduction in the production of enzymes (glucocerebrosidase) that break down lipids (glucocerbrosides). This leads to problems in lysosomes (as described above) and the accumulation of alpha synuclein (a protein found in healthy neurons).  Most people with Parkinson’s disease have Lewy Bodies or clumps of alpha-synuclein.

Both of these research areas are clearing up what is happening on a cellular level in Parkinson’s disease. One of the areas of active research is in developing therapies that will restart, intervene or increase the speed of protein recycling, another area is in creating interventions to stop mitochondrial oxidative stress.

We will address other areas of research and upcoming treatment therapies in a future post.