Causes, Pathological Mechanisms, and Lessons from Biology
Roughly 15% of Parkinson's disease patients have a first-degree relative who also has/had Parkinson's disease; this suggests that genetics play a consequential role in the development of familial Parkinson's disease.31 Roughly nine genetic mutations have been associated with Parkinson's disease; of these, six have been particularly well characterized.31,32 Mutations in these genes are generally associated with early onset Parkinson's disease, which is diagnosed before age 40; Parkinson's disease of genetic origin is sometimes diagnosed in childhood.
Mutations in the following genes are associated with an increased risk of Parkinson's disease:
Additional research is required to fully elucidate the role of genetics in Parkinson's etiology; it is likely that several additional genes involved in the pathology will be identified in the coming years. Treatments based upon genetic therapy are likely to become more widespread and therapeutic as scientific knowledge progresses.
Genetic testing for mutations known to be associated with Parkinson's disease is available through genetics health care professionals. Specifically, tests are available that check for mutations in PINK1, PARK7, SNCA, and LRRK2. Although the testing is expensive, and accuracy is a potential concern, those individuals with a family history of Parkinson's disease are encouraged to discuss genetic testing with their healthcare provider.
The National Human Genome Research Institute, a division of the National Institutes of Health, has compiled further information about the role of genetics and genetic testing in Parkinson's disease. This resource can also assist with the location of a genetic counselor near you. Their website is: http://www.genome.gov/10001217#4.
Individuals found to have a mutation in one or more of the genes linked to Parkinson's, as well as those with a family history of Parkinson's, should consult a Parkinson's disease specialist, and initiate nutritional and lifestyle strategies to combat neurodegeneration.
A flurry of emergent research has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease. Mitochondrial dysfunction results in impaired ATP generation, loss of cellular repair mechanisms, and cellular inefficiency.
As mitochondria become dysfunctional they generate large quantities of free radicals, which contribute to oxidative stress that, in turn, causes further mitochondrial dysfunction. Concurrently, loss of mitochondria to oxidative damage means fewer mitochondria are available to meet the energy demands of the cell to repair damaged components. The cascade of mitochondrial dysfunction, oxidative stress, and loss of mitochondria form a continuity that ultimately leads to cell death.52,53
Numerous studies have clearly identified mitochondrial dysfunction as a central pathological feature of both genetic and sporadic Parkinson's disease.54,55 Moreover, many of the genes that confer predisposition to familial Parkinson's are intimately related to mitochondrial function; much of the neuronal death in Parkinson's of genetic origin is due to mitochondrial dysfunction, and impaired mitophagy.56-58 While several factors, including exposure to environmental toxins,56,59,60 also contribute to mitochondrial dysfunction in the substantia nigra, age-related mutations in mitochondrial DNA are thought to be a primary culprit.60,61 Alarmingly, dopamine itself, and L-DOPA, may contribute to mitochondrial toxicity in dopaminergic neurons.62-64
Mitophagy, Lewy Bodies, and alpha-Synuclein
Damaged mitochondria are continually being cleared from within the cell through a process calledmitophagy. Mitophagy, a type of autophagy, is a kind of cellular recycling system that clears damaged mitochondria before they can accumulate and cause cellular dysfunction. However, age-related mutations in mitochondrial DNA, which cause mitophagy to become less efficient, coupled with an ever-intensifying propensity for endogenous and environmentally mediated mitochondrial damage cause the neuronal mitophagic system to become overwhelmed.57,65 Over time, damaged mitochondria build up inside the neuron, leading to cell death. Not surprisingly, several of the genetic mutations linked to familial Parkinson's disease cause disturbances in mitophagy.57,58
Another toxic byproduct of mitochondrial dysfunction and impaired mitophagy is the formation of Lewy bodies. Lewy bodies form as reactive oxygen species derived from dysfunctional mitochondria damage structural components of the cell called microtubules. As microtubules are damaged, they release a protein called alpha-synuclein. The loose alpha-synuclein proteins then group together, or aggregate, and form a toxic mass (a Lewy body) that further damages the cell. Moreover, alpha-synuclein has been shown to directly interfere with mitochondrial function and inhibit ATP synthesis, furthering the spread of mitochondrial dysfunction in the brains of Parkinson's disease patients.66-68 Over time, Lewy bodies spread to neighboring cells, damaging neurons within the vicinity of a dead or dying neuron.69
Lewy bodies share some characteristics with toxic proteins that develop in the brains of patients with Alzheimer's disease and other neurodegenerative diseases, primarily in that they cannot be broken down and cleared from the cell by normal autophagic (cellular house cleaning) actions.
The Role of Inflammation in Parkinson's Disease
Inflammatory responses contribute to the perpetuation of neurodegeneration in Parkinson's disease. The brain contains immune cells called microglia, which are known to be activated in Parkinson's disease.70,71 Upon activation, microglia release inflammatory cytokines that can spread to nearby healthy neurons and cause degeneration. Dopaminergic neurons in the substantia nigra, the brain region most affected by Parkinson's disease, express receptors for an inflammatory cytokine called tumor necrosis factor-alpha (TNF-α), which suggests that excess TNF-α released by nearby activated microglia may damage nigral dopaminergic cells.
Elevated cytokines in the brain of those with Parkinson's disease is a consequence of neurodegeneration.72 In experimental models, exposure to the neurotoxin MPTP (a chemical used to induce Parkinson's disease in experiments) leads to death of dopaminergic neurons. Interestingly, in monkeys, inflammation is increased even years after initial exposure to MPTP.71 This suggests inflammation, once initiated, has long-term consequences in Parkinson's disease.
As dopaminergic cells succumb to either environmentally or genetically induced mitochondrial dysfunction, they release free radicals. These free radicals then activate nearby microglial cells, which in turn, excrete inflammatory cytokines that bind to and damage nearby dopaminergic neurons. This positive feedback loop may continue over years or even decades and slowly contribute to the loss of dopaminergic neurons that leads to Parkinson symptoms.72,73
Epidemiological studies on the use of anti-inflammatory drugs and the risk of Parkinson's onset are conflicting. Some studies suggest a protective role of ibuprofen, but not other anti-inflammatory drugs.74 However, a large study published in the British Medical Journal involving over 22,000 subjects found no association between use of any NSAID reduced risk.75 These findings reinforce the notion that, rather than initiating dopaminergic cell death, inflammation may perpetuate it, thus contributing to Parkinson's disease progression. Life Extension believes that suppressing inflammation may slow disease progression in Parkinson's disease patients.
Simvastatin as an Anti-Inflammatory and Neuroprotective Agent in Parkinson's Disease
Groundbreaking research suggests that the cholesterol lowering drug simvastatin may provide powerful neuroprotection in Parkinson's disease. A little-known fact among the public is that statin drugs do more than simply lower cholesterol, they are also anti-inflammatory agents. In fact, many researchers believe that some of the cardiovascular benefits are due to their anti-inflammatory properties.76
Simvastatin is efficient at crossing the blood-brain barrier, and it has been shown to exert potent anti-inflammatory and neuroprotective action in the dopaminergic tract.77,78
In animal models, simvastatin was shown to attenuate the neurotoxicity of MPTP. In fact, simvastatin accumulated in the nigra and suppressed microglial activation, leading to reduced expression of inflammatory cytokines and increased dopaminergic neuroprotection.79 Another animal experiment found that simvastatin was able to completely reverse the decline in dopamine receptors associate with exposure to the neurotoxin 6-hydroxydopamine.80
In a large human clinical study involving over 700,000 subjects, use of simvastatin was associated with a 49% reduction in the likelihood of onset of Parkinson's symptoms, as well as a 54% reduction in the risk of dementia, suggesting a substantial neuroprotective effect.81
Due to the emergence of strong evidence that simvastatin may have anti-inflammatory and neuroprotective actions, Life Extension encourages those Parkinson's disease patients taking a cholesterol-lowering medication to talk with their doctor about switching to simvastatin. Even those whose cholesterol is not significantly elevated may benefit from low-dose simvastatin—those not taking cholesterol-lowering medication should discuss this with their doctor.
Importantly, those taking any statin drug should be aware that statins deplete coenzyme Q10 (CoQ10) levels. If taking statins, supplement with CoQ10 and ensure maintenance of healthy CoQ10 blood levels by periodically having a CoQ10 blood test.