Parkinsons disease is one the most common neurodegenerative disorders, yet it remains one of the most mysterious to date. People diagnosed with Parkinson's disease exhibit symptoms such as tremors, rigidity, akinesia and muscle stiffness. Looking across a wide range of different affected individuals, neuroscientists are still undecided as to what the true cause of Parkinson's disease may be, due to a culmination of different factors at work - both genetic and environmental.
In all Parkinson's disease patients, there is the death of dopaminergic cells, and hence depletion of dopamine, which is an essential neurotransmitter responsible for regulating processes such as hunger, sleep but most importantly, motor function. This lack of dopamine will lead to an imbalance of neurons directly involved in motility, affecting normal motor function. What might be the cause of dopaminergic neuronal cell death?
Apoptosis gone wrong
To begin, we must consider apoptosis, a programmed cell death which is 'written' within our genes. It is a natural process that enables the removal of dysfunctional or superfluous cellular entities. Breakdown of dopaminergic cells occurs in the substantia nigra, located in the midbrain, and this degradation is by no means abnormal. All cells in the body will undergo decay due to apoptosis, but for Parkinson's disease patients, the rate of cell apoptosis far outweighs the rate of cell renewal/growth, i.e. more cells are dying than are replenished by new cells.
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This accelerated dying may possibly be linked to disruptions within the ubiquitin pathway (McNaught et al. 2002), one of the many signal transduction pathways with a specific function of clearing waste products intra and extracellularly. The main protein operating within the ubiquitin pathway is called ubiquitin, named so because it is 'ubiquitous' throughout the human body. This protein will attach onto certain waste products, such as degenerate organelles or proteins to 'mark' them for destruction. The elimination is then carried out by one of two means, either through the isolation of waste products using lipid membranous sacs, then fusion with a nearby lysosome, which carries digestive enzymes necessary for breakdown, or via proteasomal degradation (Ciechanover, 2005).
A few theories have surfaced within the past two decades implicating disruptions to parts of the ubiquitin pathway in Parkinson's disease. McNaught et al B. (2002) investigated the proteasomal activity in patients with Parkinson's disease and found a significant loss of the regulatory 20S α-subunit, and only in the substantia nigra. They concluded that this may impair normal degradation of waste products, allowing them to accumulate and become toxic.
Another theory suggests that Parkinson's disease is linked to genetic defects of parkin and PINK1, which regulate mitochondrial activity in cells. Parkin (Narendra et al., 2008) and PINK1 appear to have a role in degradation of dysfunctional mitochondria. Parkin is a ubiquitin ligase that is involved in selectively attachment of ubiquitin units onto mitochondria of cells. Mutations in parkin have been associated with reduced mitochondrial breakdown (Lee et al., 2010). It was similarly shown that PINK1 normally aggregates in damaged mitochondria to facilitate their removal from the cell, but suppression of PINK1 or mutations severely impair this process (Narendra et al., 2010). The dysfunctional mitochondria release harmful oxidants, which cause extensive damage within the cell, often by oxidising proteins such as ubiquitin. Also, the role of mitochondria is to provide energy in the form of ATP to eukaryotic cells, via a process called cellular respiration. In people affected with Parkinson's disease, the mitochondria fail to function properly, producing less ATP. Furthermore, certain chemical toxins can impair mitochondrial activity by inhibiting passage of free electrons through the protein complex 1 in the final stage of cellular respiration (oxidative phosphorylation).
There also appears to be a common feature of all Parkinsons's disease patients - appearance of Lewy bodies (See Fig. 1). These are aggregates of a protein comprised mainly of α-synuclein, which is very difficult to degrade from the cell, and can become cytotoxic if allowed to accumulate (Xu et al., 2002). It is supposed that there is may be mutations of the gene(s) that encodes that protein causing the product to become misfolded with higher binding affinity (Cookson, 2009). As the shape of a protein is central to its function, then misfolding can have drastic consequences on the fate of the protein. Many studies suggest that these mutations can lead to a multitude of problems such as reduced lysosomal activity, impaired proteasomal degradation and mitochondrial dysfunction. (Stefanis et al., 2001) However it is still not known to what extent α-synuclein and Lewy bodies plays a causal role in neuronal cell death.
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Fig. 1: Mitochondrial dysfunction leads to release of strong oxidants that affect protein function.A very common theory underlying Parkinson's disease pathology is causation by oxidative stress. All reactive oxidants and free radicals can contribute to oxidative stress. This implies anti-oxidants can help to alleviate symptoms, and reduce the risk of developing Parkinson's disease. For instance, epidemiological studies suggest that there is an inverse correlation between
smoking and Parkinson's disease is both men and women (Hernan et al., 2001). This may be due to increased levels of reducing carbon monoxide in circulation.
Common environmental toxins may exert their effects by oxidative stress, such. The Parkinsonian effects of MPTP were discovered in the 1980s, when a group of drug users in California took cocaine contaminated with MPTP. They were stricken with symptoms characteristic of Parkinson's disease. The effects were shown to be irreversible, and quickly brought attention to the existence of environmental causes of Parkinson's disease. It is now known that MPTP is metabolised to MPP+ via MAO-B, which can then inhibit complex I of mitochondria and prevent oxidation of NADH (Nicklas et al., 1985; Jenner, 1989).
Rotenone, another possible culprit implicating the disease is widely used in chemical pesticides. Because it is lipophilic, it has easy access into all organs, including the brain. Studies suggest that rotenone causes mitochondria dysfunction, by impairing oxidative phosphorylation, through inhibition of activity at complex I (Betarbet et al., 2000). This inhibition, although affecting the whole brain produces selective degeneration of dopaminergic cells. Sherer et al. (2003) hypothesised that the toxicity of rotenone is associated with increased oxidative stress, often arising from the production of reactive oxygen species in complex I. This was supported by results that showed increased resistance to cell death when an antioxidant was added. However, because ingestion is the main point of exposure to the substance, very few cases of Parkinson's disease have been accredited to it. However, on a demographic scale, it appears that people who are more exposed to it, for instance in agricultural areas, have a greater risk of being affected by the disease.
Scientists have come a long way in modelling Parkinson's disease, discovering how interplay between toxins and deficiencies in cellular processes, such as waste breakdown, may affect Parkinson's Disease. However, they are still a long way off from finding a clear solution. This is primarily due to the fact that there is no single explanation, since both genetic and environmental factors exist. As such there is no complete model for Parkinson's Disease - case variation applies.