Unraveling Parkinson's Disease

Parkinson’s disease is defined as “a disorder of the brain that leads to shaking (tremors) and difficulty with walking, movement, and coordination.”¹ It typically affects people after the age of 50 and has been linked to multiple genetic mutations. Dominant forms of the disease are typically linked to mutations in two genes, alpha-synuclein and dardarin, while recessive forms are linked to mutations in PD, parkin, DJ-1 and PINK-1.²
What is going on in Parkinson’s disease? Parkinson’s patients show a loss of neurons in the brain which release a specific neurotransmitter, dopamine. This loss of dopamine inhibits signals from the brain to the muscles, making muscle control very difficult – this leads to tremors and uncontrollable movement. Furthermore, certain proteins, including one called α-synuclein, build up in the brain of Parkinson’s patients. Masses of these proteins in the body are called Lewy bodies.³
Recent research has shown that Parkinson’s disease is intricately related and dependent upon a signal transduction pathway called the MAPK pathway. The MAPK pathway is a cascade of kinases, or proteins which add a molecule, phosphate, to other proteins. These pathways are often difficult to sort out, but each protein has a pretty simple task – add a phosphate to the next protein which will then become activated and do the same. After many of these phosphorylations, a protein will eventually exert some effect on the cell such as changing DNA expression or signaling cell death (aka apoptosis).
How does MAPK pathway affect Parkinson’s? One way is through α-synuclein’s effect on the central nervous system. When α-synuclein builds up in the brain, the MAPK pathway is stimulated. This stimulation then leads to activation of two types of nervous system supporting cells called astrocytes and microglia. Activated astrocytes and microglia can then go on to produce cytokines (or signaling peptides) which lead to inflammation. Inflammation oftentimes results in neuron death as the brain attempts to rid the body of an abnormal cell.
Another effect α-synuclein has on the cell is that it stresses mitochondria, the energy-producing organelle of the cell. Stressed mitochondria can produce reactive oxygen species (ROS) which can damage the cell. These ROS’s can then stimulate more microglia to cause an inflammatory response. Stressed mitochondria can also produce cytochrome c, a protein which can signal cell death, or apoptosis. Furthermore, the MAPK pathway phosphorylates p53, a protein in the cell. p53 can cause production of Bax, a protein which signals for apoptosis.³

There’s one thing in this story that is very clear: MAPK has a very important role in Parkinson’s disease. There seems to be many intricate loops, cascades, and proteins involved in the web which is Parkinson’s – and the MAPK pathway makes many appearances in this web. Hopefully in the future we can utilize our knowledge of this pathway to create treatments for this very debilitating disease.
1. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001762/
2. http://www.ncbi.nlm.nih.gov/pubmed/16026116
3. Kim, E.K., Choi, E. Pathological roles of MAPK signaling pathways in human diseases. Biochimica et BIophysica Acta. 1802 (2010) 396-405.
4. http://www.sciencephoto.com/