Exp Neurobiol 2012; 21(3): 123-128
Published online September 30, 2012
© The Korean Society for Brain and Neural Sciences
Department of Neurology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan
Correspondence to: *To whom correspondence should be addressed.
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To date, numerous case-control studies have shown the complexity of the pathogenesis of Parkinson's disease (PD). In terms of genetic factors, several susceptibility genes are known to contribute to the development of PD, including α-synuclein (
Keywords: Parkinson's disease, environmental factor, genetic factor, environmental-genetic interaction
Multiple factors influence the pathogenesis of sporadic Parkinson's disease (PD). In terms of genetic factors, several susceptibility genes are known to contribute to the development of PD. Environmental factors are also known to be involved. In addition, aging is closely related to the development of PD because of its effects on neurodegenerative disorders. Studies have been conducted to determine the extent to which genetic or environmental factors contribute to the etiology of PD, including twin studies conducted by Tanner in 1999 . In this work, the concordance of PD within pairs of twins was assessed and compared between homozygous and heterozygous twins. The results indicated that no genetic component is involved in cases where the disease begins after the age of 50 years, but that genetic factors are important with PD onset before the age of 50. We have now learned about the complexity of PD pathogenesis. However, studies that are more recent have extended this earlier finding, providing a better understanding of the complexity of PD pathogenesis. A particularly important recent finding in this field is that environmental-genetic interactions contribute more to the pathogenesis of PD than do genetic factors or environmental factors alone.
Familial forms of PD have been reported by clinicians involved in extensive, long-term studies. The Contursi kindred, which is one of the largest and most intensively investigated families, is an Italian family with an autosomal-dominant form of familial PD . In this group, the clinical features are characterized by an average age for PD onset of 46 years, average duration between disease onset and death of 9 years, and neurological signs of progressive parkinsonism with good response to levodopa treatment as well as cognitive dysfunction and psychiatric features. These characteristics cannot be distinguished from those of sporadic PD, with the exception of earlier disease onset. In 1997, it was found that all affected individuals in this family have a point mutation in the α-synuclein (
A second intensively investigated family, the Iowa kindred, has another genetic form of PD with a different
In addition to
The discovery of
In general, younger age at onset is observed in most patients with the familial form of PD, but no other specific clinical features can distinguish familial from sporadic cases. In addition, not all patients have a positive family history, either because inheritance is recessive or low penetrance of a dominant mutation. Hence, a positive family history is an unreliable sign for distinguishing between "genetic" and "non-genetic" forms of PD.
What roles do environmental factors play in the pathogenesis of PD? MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was identified as the first exogenous chemical that could lead to the development of a human neurodegenerative disease. This discovery occurred in 1983 when MPTP was accidentally created as a byproduct of synthetic opioid production. Four individuals developed marked parkinsonism after intravenous MPTP administration . MPTP is a neurotoxic precursor to 1-methyl-4-phenylpyridinium (MPP+), which causes permanent symptoms of PD by destroying dopaminergic neurons in the substantia nigra. A neuropathological study revealed selective neurodegeneration in the nigrostriatal pathway in individuals who had been exposed to MPTP . These cases illustrate that exogenous materials can cause human neurodegenerative disease, although the exact mechanism is not clear. In addition to MPTP, numerous recent epidemiological studies have shown that several other environmental factors are either risk factors for PD or protective factors against PD. Identified risk factors include herbicides and pesticides (e.g., paraquat, rotenone, and maneb), metals (e.g., manganese and lead), head trauma, and well water. In contrast, smoking and coffee/caffeine consumption are known to be protective against PD. Those who currently smoke are protected to a greater extent against PD than those who previously or never smoked. In addition, the duration of smoking is more important than smoking intensity for protection against PD. Furthermore, consumption of coffee/caffeine has been shown to be protective against PD in a dose-dependent manner.
In a study based on the Honolulu Asian Aging Study, 8,004 male Japanese immigrants were enrolled between 1965~1968 in Hawaii . During an average follow-up period of 30 years, PD developed in 102 cases. From these data, the relationships between smoking and coffee consumption and the onset of PD were assessed. In the non-smoking group, coffee consumption showed a clear inverse relationship to the development of PD. In addition, the group of current smokers showed a low incidence of PD. These findings indicated that higher coffee/caffeine intake is associated with a significantly lower incidence of PD and that this effect appeared to be independent of smoking.
More recent studies indicated that environmental-genetic interactions play significant roles in the development of PD. An example is related to cytochrome P450 (CYP) 2D6, one of the CYP superfamilies of enzymes, which metabolizes several xenobiotics in the liver, including organophosphate pesticides, the herbicide atrazine, and MPTP. In general, the activity of
So-called "poor metabolizers," those showing deficient enzymatic activity of
Another example of environmental-genetic interactions relates to solute carrier family 6 member 3 (
The next example of environmental-genetic interactions relates to the monoamine oxidases (MAO), which are enzymes that catalyze the oxidation of monoamines in the brain. In the case of
As another example of genetic-environmental interactions, glutathione S-transferase (GST) is related to the antioxidation and detoxification of endogenous and xenobiotic substrates. Among
Organophosphates are recognized as neurotoxins and have been identified as environmental risk factors for PD in some studies. The genotype of paraoxonase 1 (PON1) has been shown to determine the level of susceptibility to the detrimental effects of organophosphate exposure, including the insecticides diazinon and chlorpyrifos. It has been speculated that those with
It is known that caffeine protects neurons against degeneration by blocking adenosine receptor A2A (ADORA2A). In addition, caffeine is primarily metabolized by CYP1A2, which indicates that CYP1A2 enzyme activity might influence neuroprotection in PD patients. Furthermore, a very recent report revealed an association between certain
Many studies have reported associations between genetic polymorphisms and PD. Even if such studies fail to generate significant results, some genes might be found to have significant roles if their interactions with environmental factors are examined (Table 1). Recent studies have revealed that certain interactions promote the development of PD: between the
Table 1. Environmental-genetic interactions in Parkinson's disease