The Pathophysiology of Parkinson's Disease

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 of 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 proper neurological function, why would they accumulate in individuals with neurological diseases?" In the presence of a couple different scenarios, these types of proteins begin to accumulate, or clump together and damage the neurons where they accumulate. This process is called ubiquitination.