What may be an additional relief to many coffee drinkers, caffeine consumption appears to protect against PD. Epidemiologic and pre-clinical data suggest that caffeine may confer neuroprotection against the underlying dopaminergic neuron degeneration, and may delay the onset and progression of PD. Caffeine is thought to be the responsible component, since total caffeine intake and intake of caffeine from non-coffee sources were found to be inversely correlated to PD risk, whereas no association was found between other components in coffee and the risk of PD.
Caffeine is an inhibitor of the adenosine A2 receptor and seems to improve motor function in a mouse model of PD. Caffeine may also improve the motor deficits of human PD, as adenosine A2A receptor antagonists such as istradefylline, reduces the “off” time and dyskinesia (impairment of voluntary movements) associated with standard dopamine replacement treatments at the end of a dose period. Finally, caffeine may help to alleviate some of the non-motor symptoms of PD, which are not benefited by dopaminergic drugs. Altogether, studies provide strong evidence that caffeine may represent a promising therapeutic tool for PD to alleviate both motor and non-motor early symptoms with its neuroprotective potential (Kalda et al., 2006).
Many epidemiologic studies have also shown a reduced risk of PD among cigarette smokers, to as low as 40% compared to non-smokers. Several mechanisms may explain the potential neuroprotective effect of cigarette smoking, and they likely involve nicotine, because nicotine may stimulate dopamine release, act as an antioxidant, or alter activity of the enzyme monoamine oxidase B. Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect. Certainly tobacco smoking is a severe health hazard in its own right, though understanding its mechanistic relationship, probably through the actions of nicotine, to a diminished risk of developing PD may provide novel therapeutic avenues.
Antioxidants, such as vitamins E and C, have been proposed to protect cells against oxidative damage by neutralizing free radicals. Clinical trials of vitamin E supplements for PD have shown no effect on primary endpoints, such as when there is need to start levodopa therapy. The results regarding fat and fatty acids have also been contradictory, with various studies reporting protective effects, risk-enhancing effects, or no effects. There are some indications of a possible protective role of estrogens (lower incidence in women) and anti-inflammatory NSAID drugs, though more study is needed to understand the mechanisms and scale of those effects.
Parkinson’s disease is usually idiopathic (having no known cause). Many PD cases may also arise from environmental components and exposures. A small number of genes are known to be involved in up to 6% of PD cases, and there are probably other genes that increase the potential risk of PD without necessarily causing it. Though PD is not generally considered a genetic disease, up to 15% of patients have a direct family member who has also had PD. As genome technologies continue to improve and be reduced in cost, genetic links and associations may become more clear with time and greater sequence information from patients afflicted with PD. Entire genome sequence analysis can be performed on individual patients at a reasonable and ever-decreasing price.
Mutations in at least seven genes have been linked to either dominant or recessive early-onset familial forms of PD. Additional loci segregating with inherited PD have been identified, with the causative genes to be identified by further study. Known PD genes code for:
People with mutations in these genes will develop PD, though they only account for a small percentage of the total cases, with the largest component being the LRRK2 mutations in about 5% of cases. Genome studies have now revealed that mutations in these genes do show up in multiple cases of the sporadic PD. Most likely, mutations in these genes result in cellular alterations that are similar to those seen in sporadic PD and likely include impaired mitochondrial function and dynamics, increased oxidative stress sensitivity, and abnormal protein aggregation (Kumar et al., 2011).
Mutations in three known genes—SNCA (PARK1), UCHL1 (PARK5), and LRRK2 (PARK8)—and one mapped gene (PARK3) result in autosomal dominant Parkinson’s disease (one bad copy of two is sufficient to cause disease). Mutations in three known genes—parkin (PARK2), DJ-1 (PARK7), and PINK1 (PARK6)—result in autosomal recessive Parkinson’s disease (requires both gene copies to be mutated for disease) and have been linked to the early onset inherited forms of PD. These three autosomal recessive genes appear to form a protein complex that is important in the degradation of some proteins. Three susceptibility genes have been identified and more may become known as more complete DNA sequencing analysis of patients is performed. Molecular genetic testing is clinically available for the most common mutated alleles of PARK2, (the gene-encoding parkin), PINK1, PARK7, SNCA, and LRRK2.
Traditionally, the presence of Lewy bodies was required for pathologic confirmation of Parkinson’s disease after death. However, with the discovery of new subtypes of Parkinson’s (eg, PARK2 juvenile onset PD), it has been recognized that nigral pathology may occur in the absence of Lewy bodies, and that therefore the Lewy bodies may not be the primary cause of disease pathology.
The SNCA gene (PARK1) encodes alpha-synuclein protein, the main component of Lewy bodies and the noted pathology marker in autopsy slides of PD brains. Mutations of the SNCA gene include single nucleotide changes, or duplications and triplications of the gene locus. Extra copies via duplication of the SNCA locus account for about 2% of familial cases, though not all persons where they are found have yet developed PD. Perhaps simple overexpression of the gene, via too many copies, is sufficient to cause it to precipitate into aggregated inclusion bodies, with subsequent triggering of damage control or apoptosis of the cell. The mean age of onset in individuals with mutations in this gene is 46 years.
The LRRK2 gene (PARK8) encodes for a protein called dardarin. Nearly a dozen different mutations have been reported in the LRRK2 gene. Most of these prevent LRRK2 from localizing properly in the cell and instead the protein pools inside the cell, possibly resembling inclusion bodies with reduced degradation. Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases. Sergey Brin, a cofounder of Google, has a known mutation in this autosomal dominant gene for PD, with the resulting 20% to 80% chance of developing PD; his mother, carrying the same mutation, already has PD.
The parkin (PARK2) type of juvenile-onset parkinson disease, originally described in Japanese individuals, is characterized by typical Parkinson’s disease features, often with lower-limb dystonia (a movement disorder that causes the muscles to contract and spasm involuntarily) and onset between age 20 and 40 years. Disease progression is slow. Sustained response to levodopa is observed, as well as early, often severe, dopa-induced complications (fluctuations and dyskinesias). The parkin protein is found in a multi-protein E3 ubiquitin ligase complex which is part of the ubiquitin-proteasome system that mediates the targeting of cellular proteins for degradation. Most likely parkin helps degrade one or more proteins toxic to dopaminergic neurons, and when that process is defective, neurons are more susceptible to damage and early death.
Mutations in PARK2 include point mutations as well as exon coding-sequence rearrangements, including both deletions and duplications. Of the patients with onset of PD prior to age 40, 18% had parkin mutations, with 5% having two identical homozygous mutations. Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).
PARK7, (previously known as DJ-1) encodes a ubiquitous, highly conserved protein (protein DJ-1) that may play a role in defense against oxidative stress. Two mutations have been found: one with a deletion of several exons, which prevents any synthesis of the DJ-1 protein, and another that is a point mutation at a highly conserved residue (L166P). That mutation makes the protein less stable and promotes its degradation through the ubiquitin–proteasome pathway, thereby reducing the amount of DJ-1 protein to low or absent levels.
PINK1 (PARK6) encodes a protein called PTEN-induced putative kinase 1. This protein is found in cells throughout the body, with highest levels in the heart, muscles, and testes. Within cells, the protein is located in the mitochondria, the energy-producing centers that provide power for cellular activities. It appears to help protect mitochondria from malfunctioning during periods of cellular stress, such as unusually high energy demands.
More than seventy mutations that can cause Parkinson’s disease have been found in the PINK1 gene. By studying these mutations, scientists hope to unravel the mechanisms underlying the disease process that may lead to new therapies. When fruit flies carrying PINK1 mutations were given vitamin K2, the energy production in their mitochondria was partially restored and the insects’ ability to generate energy to fly was improved. Researchers were also able to determine that the energy production was restored because the vitamin K2 had improved electron transport in the mitochondria. This in turn led to improved ATP and energy production in the muscles used for flight.
Vitamin K2 plays a role in the energy production of defective mitochondria. Because defective mitochondria are also found in Parkinson’s patients with a PINK1 or Parkin mutation, vitamin K2 potentially offers hope for a new treatment for PD.
For many years, it was thought that most forms of Parkinson’s disease did not result from a genetic contribution; however, by the late 1990s, studies in different patient populations documented that the risk of Parkinson’s disease among first-degree relatives of an affected individual is 2 to 14 times higher than the risk in the general population. With evidence of a genetic component for PD, families with two or more members who had PD were studied. Results suggest the presence of PD susceptibility genes that may increase the risk for familial PD.
A single mutation in GBA, the gene encoding glucocerebrosidase, may convey up to a 5-fold increased risk for PD. Individuals with two GBA mutations have Gaucher disease, which is also found at a high rate among Ashkenazi Jews. It remains to be seen if the risk for PD is as strong in other populations as it is in those heterozygous carriers of Gaucher disease.
Mitochondrial impairment, particularly with regard to complex I of the electron transport chain, has been implicated as a cause of PD. Individuals that had one particular variant in the NADH complex I enzyme had a significantly lower risk of PD than others who had the most common form of the enzyme, suggesting that variation in complex I proteins is an important risk factor in PD susceptibility. Mitochondrial DNA deletions have also been found to be common in the substantia nigra neurons of individuals with Parkinson’s disease, cells where mitochondrial dysfunction has been shown to be immediately causative of PD in the MPTP neurotoxin model discussed earlier.