In a past post on the history of Parkinson's disease, I discussed a little bit about how we have arrived at our current understanding of this very prevalent neurodegenerative condition. In this blog post, we will discuss how Parkinson's Disease develops on a cellular level.
As a quick recap from our previous post, scientists have determined that the main neurological structure involved and Parkinson's disease is a part of the midbrain called the substantia nigra pars compacta; The area involved with producing dopamine, which is a mood, emotion, arousal, and movement neurotransmitter. Scientists have also determined that one of the cellular mechanisms that are associated with Parkinson's disease, is an accumulation of a protein called alpha-synuclein. Alpha-synuclein is an intracellular protein that is found mainly in neurological tissues but is also found in small quantities in heart muscle as well as some skeletal muscle. Despite its diffuse presence in tissue, the function of alpha-synuclein it's still not completely understood. However, leading researchers believe that it is intimately involved with the transport of neurotransmitters, particularly dopamine. Some researchers believe that it functions as a structural protein, called a microtubule-associated protein, or MAP, very similar to the other protein (tau protein) found accumulated in neurodegenerative conditions, such as Alzheimer's disease. The function of these MAP proteins is thought to facilitate the transportation of neurotransmitters from the cell body to the part of the neuron that communicates with other neurons, called the synaptic cleft. These microtubule-associated proteins of tau and alpha-synuclein either maintain the integrity of the transport tubules or facilitate the release of the neurotransmitters, respectively. Some studies have shown that mice lacking alpha-synuclein show an increase in dopamine release in movement-sensitive areas of the brain. Other studies in mice show that decreasing alpha-synuclein is detrimental to neurological functions, particularly with spatial learning, and working memory. Alpha-synuclein has been shown to be involved in calcium regulation, mitochondrial function, and modulation of calcium-gated voltage channels on neurons. Other studies show that alpha-synuclein actually serves to regulate dopamine levels, to protect an individual from dopamine toxicity, by blocking dopamine transporters and re-uptake. So the question becomes, "if these proteins have a purpose for maintaining the proper neurological function, why would they accumulate in individuals with neurological diseases?" In the presence of a couple of different scenarios, these types of proteins begin to accumulate, or clump together and damage the neurons where they accumulate. This process is called ubiquitination.
Ubiquitination is the process by which a polypeptide called ubiquitin (which is found everywhere in our body, as the name would suggest), is attached to a substrate protein, such as alpha-synuclein. Think of this process as Velcro touching your favorite cashmere sweater. In this example, the Velcro would be ubiquitin, and your sweater is alpha-synuclein. When the ubiquitin sticks to alpha-synuclein it causes the protein to fold over and stick to itself, and clump together. Independently, they are not sticky, but when they touch, they join and are difficult to separate. When these proteins begin to accumulate and clump together, they form what are called Lewy Bodies.
Lewy Body disease is named after the neurologist, Dr. Frederick Lewy, who discovered them while working with Dr. Alois Alzheimer in the early 1900s. (Dr. Lewy is standing on the right, with Dr. Alzheimer standing third from the right). Photo courtesy of the Alzheimer's Association. You may be thinking that we need to determine a way to stop ubiquitination. However, this process is very important in certain functions like mitosis, antibody-antigen responses, apoptosis (or programmed cell death of unhealthy cells), the formation of intracellular organelles and ribosomes, synaptic vesicle transportation, etc. In light of its importance, the scientific community is focusing efforts on trying to determine is what causes ubiquitination to become deregulated and target these dopamine-producing neurons. Researchers have identified a number of different situations that seem to promote ubiquitination:
As alpha-synuclein goes through the ubiquitination process and Lewy bodies begin to form, they render the neurons in that area begin to lose their ability to transmit neurological impulses, decrease their ability to produce neurotransmitters, and dysfunctional. It is estimated that at the time of death, an individual with Parkinson's Disease will have lost approximately 60% of their functional brain tissue to Lewy Body disease. In my next post, we'll discuss the 6 stages of Lewy Body inclusions, termed Braak's Staging.
More reading: Alexander, G. E. (2004, September). Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. Retrieved June 17, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181806/ Greffard S, Verny M, Bonnet AM, et al. Motor score of the Unified Parkinson Disease Rating Scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch Neurol. 2006;63:584–588. Retrieved June 17, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/16606773 Olanow CW, Kieburtz K, Schapira AH. Why have we failed to achieve neuroprotection in Parkinson's disease? Ann Neurol. 2008;64 2:S101–S110. Retrieved June 17, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/19127580