When Environment and Genes Meet, the Mix Might Be Parkinson Disease

Theories about the causes of Parkinson disease (PD) are as tangled as the neurofilament proteins of Lewy bodies. However, investigators are teasing out threads of evidence that increasingly implicate environmental factors--perhaps aided and abetted by genetics--as contributors to this common neurodegenerative disorder.

Several observations and events have led investigators to speculate that exposure to environmental toxins or pesticides might play a role in PD:

•The relative risk of PD is higher in industrialized countries than in nonindustrialized countries.¹

•PD is more common in agricultural workers than in other groups.¹

•In the 1980s, an outbreak of severe PD was noted in heroin addicts. The cause was 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), a contaminant found in synthetic heroin that causes neurochemical, pathologic, and clinical symptoms that resemble those of idiopathic PD. The observations showed that parkinsonism can be chemically induced. However, investigators following MPTP-induced parkinsonism believe that PD pathogenesis is most likely related to a combination of events: the interaction between toxins and genes or exposure to multiple toxins.^2,3

Metals, such as iron and copper, have been studied as possible agents of PD development because of their ability to accumulate in the substantia nigra and to also cause oxidative damage. Recent evidence shows that metals interact with a-synuclein and promote its fibrillation in vitro, opening the door to the possibility that they contribute to the formation of Lewy bodies.⁴ Additional support for the "metal as the bad guy" hypothesis is the discovery that PD is more prevalent in workers with long-term exposure to lead, iron, or copper.⁵

Numerous epidemiologic studies link pesticide exposure with a high risk of PD.^6,7 This relationship appears to be dose-dependent, with the risk for PD increasing with the duration of exposure to pesticides. A study from Taiwan, for instance, found a strong association between exposure to paraquat, an herbicide sprayed on rice fields, and PD. In this study, the risk of PD increased 6-fold in persons exposed to paraquat for more than 20 years.⁶ Organochlorine and carbamate are other pesticides that have been linked with PD.⁶

Like metals, the pesticides paraquat and rotenone increase protein fibrillation of a-synuclein.⁷ The effects of metals and pesticides are additive and are probably mediated through interaction with a-synuclein. This suggests that metals and pesticides may amplify a-synuclein pathology.^8,9

Further, viruses may be an environmental trigger for PD. Parkinson-like symptoms have been observed in some persons following influenza-like and herpesvirus infections. Viruses can sometimes cause activation of immune cells and inflammation in the substantia nigra, the area of the brain affected by PD.¹

An investigative group from Rush University Medical Center in Chicago inadvertently discovered that exposure to toxins in utero may be a risk factor for PD.¹⁰ They found that female rats given lipopolysaccharide during pregnancy gave birth to offspring that had an abnormally low number of dopamine neurons. This neuron loss was accompanied by a reduction in striatal dopamine, an increase in dopamine activity, and increased production of the proinflammatory cytokine tumor necrosis factor alpha (TNF-a)--all features of PD. As in PD, the depletion of dopamine neurons persisted into adulthood and increased as the animals aged. The investigators note that bacterial vaginosis, a common condition in pregnant women, is known to increase the levels of lipopolysaccharide and proinflammatory cytokines in amniotic fluid. Thus, bacterial vaginosis may be a risk factor for PD.

GENETIC FACTORS

Evidence from studies of twins suggests that genetics do not contribute to PD that begins after age 50 years (the most common type), but do contribute to disease that affects younger persons.¹ Tanner and colleagues¹¹ examined the occurrence of PD in monozygotic (identical) and dizygotic (nonidentical, 50% shared genes) white male twins. When the diagnosis of PD was made before age 51 years in one twin, PD was 6 times more likely to develop in a monozygotic twin than in a dizygotic twin, but if the first twin had PD diagnosed after the age of 50 years, disease concordance rates were similar in monozygotic and dizygotic pairs.

Data from twin studies have limitations. It can be difficult to estimate disease concordance rates based solely on clinical information. It is possible to have partial degeneration of nigrostriatal tissue and appear clinically normal. Twins could have similar brain lesions, but the rate of progression could differ such that only the most affected sibling shows evidence of disease.²

The findings from twin studies suggest that genetics is not the strongest determinant of susceptibility to PD.¹ It may be that the combination of genetics and environmental factors triggers the neurodegeneration that is characteristic of PD. Genes and proteins of particular interest to PD researchers because of their possible contributory role are summarized in the Table.

MECHANISMS OF TOXICITY

The mechanism by which pesticides or environmental toxins potentially cause PD has not been pinpointed, but 3 explanations are most plausible:

•Gene-environment interactions. Some persons may be more genetically susceptible to PD because of polymorphisms of specific enzymes (cytochrome P-450 [CYP], CYP2D6, and glutathione S-transferase) involved in the metabolism of pesticides. These polymorphisms influence the ability of the enzymes to detoxify neurotoxic pesticides.³

•Mitochondrial inhibition. Mitochondria have long been implicated in PD and are believed to contribute to protein aggregation, Lewy body formation, and neuron death.¹ Mitochondria also produce a large quantity of free radicals, which damage cell components through oxidative stress. Oxidative stress-related changes have been detected in the brains of persons with PD.

Mitochondria contain a group of energy-processing proteins known as complex 1. The interaction between mitochondria and certain environmental toxins increases the amount of free radicals produced by complex 1. Free radicals can modify a-synuclein in a way that causes it to clump into fibrils.¹

Support for the role of mitochondria in PD development comes from studies involving the common pesticide rotenone. Betarbet and colleagues¹² showed that rotenone, when given intravenously to rats, partially inhibited complex 1 of the mitochondria. This caused selective but progressive degeneration of dopaminergic neurons as well as motor skill deficits and other symptoms of PD. More work needs to be done to see whether other substances in the environment can also inhibit mitochondrial complex 1 and produce symptoms of PD.

The mitochondrial role in PD is not limited to complex 1. Evidence indicates that specific genetic polymorphisms in mitochondrial DNA can increase the risk of PD, while other polymorphisms have the opposite effect. Patients with PD have more mitochondrial DNA variations than persons with other movement disorders or Alzheimer disease.¹

The mitochondria also are believed to initiate apoptosis after exposure to oxidative stress or toxins. The presence of certain genes may determine the presence of cells in the substantia nigra that are programmed for death on exposure to toxins.¹

Exposure to multiple pesticides or toxins is especially important to study, because compound exposures most closely approximate what happens in daily life. Thiruchelvam and colleagues¹³ examined the effects of the pesticides paraquat and maneb in mice. Paraquat, an herbicide structurally similar to the active metabolite of MPTP, reduces dopamine levels and changes behavior when injected into the brain. Systemic administration, however, produces little evidence of toxicity. Neither paraquat nor maneb causes neurologic damage when given separately, but when combined, they can cause symptoms of PD. In this study, the mice given the toxic cocktail of maneb plus paraquat had altered levels of dopamine in the substantia nigra. The mice also had significantly diminished motor skills compared with the control mice.

Investigators at Rush University Medical Center tested their theory that animals in a proinflammatory state would be more susceptible to toxin exposure.¹⁴ They gave female rats who had received either saline or lipopolysaccharide during pregnancy a subtoxic dose of rotenone. The animals were sacrificed, and tyrosine hydroxylase-immunoreactive (THir) cell counts were performed. The combined effects of prenatal lipopolysaccharide and postnatal rotenone exposure produced a 39% synergistic THir cell loss compared with controls. This loss was associated with decreased striatal dopamine and increased striatal dopamine activity and TNF-a.

Prenatal exposure to lipopolysaccharide led to an increase in the number of reactive microglia that was further increased by rotenone exposure. It also led to increased levels of oxidized proteins and the formation of a-synuclein and eosin-positive inclusions resembling Lewy bodies. These findings suggest that exposure to low doses of environmental toxins can produce synergistic dopamine neuron losses in animals with a preexisting inflammatory state. PD may indeed result from exposure to multiple stressors.

PROTECTIVE INFLUENCES

Environmental influences are not all bad with respect to PD. Some evidence suggests that certain genes and environmental agents--most notably, caffeine and cigarette tobacco--are neuroprotective.¹⁵

With all the negative publicity accorded to cigarette smoking, its protective effect comes as a surprise--and a surprise that is significant in scope. Cigarette smoking decreases the risk of PD by as much as 50%.^16,17 It could be that smoking is an environmental modifier in persons who are similarly genetically predisposed to PD. Tanner and colleagues¹¹ examined cigarette smoking in monozygotic and dizygotic twin pairs in which one twin had PD. The investigators noted that the risk of PD was inversely correlated with cigarette smoking in a dose-related fashion. This observation was especially strong in the monozygotic twins, who are genetically identical and often live in similar environments. These findings led Tanner and coworkers to suggest that factors other than genetics and environment determine the protective effects of smoking.

While that may be true, there are other studies suggesting that cigarette smoking's protective effect might indeed be genetically mediated. A team of investigators from Duke University studied nitric oxide synthase 2A (NOS2A) and its protein product inducible NOS (iNOS).¹⁷ They wanted to determine any influence that NOS2A polymorphisms and cigarette smoking interactions had on the risk of PD.

iNOS, which generates nitric oxide as a defense mechanism in response to environmental insult but also can kill cells when it accumulates, is a contributor to neurodegenerative diseases.¹⁷ The toxic effects of nitrous oxide suggest that NOS2A is a candidate gene for PD. In this study, the investigators noted a significant association between NOS2A polymorphisms and PD. An alteration in NOS2A regulation or constant bombardment with environmental toxins could prolong the activity of iNOS, thereby contributing to the death of dopaminergic neurons.

It may be that the ability to fend off PD represents a balancing act between protective and destructive environmental influences. As the tangled web of what really causes PD begins to unravel, the threads may lead to new and improved treatments and better outcomes for affected patients. *

REFERENCES

1. National Institute of Neurological Disorders and Stroke. Parkinson's Disease: Challenges, Progress and Promise. November 2004. Available at: www. ninds.nih.gov/disorders/parkinsons_disease/parkinsons_research.htm. Accessed January 16, 2007.

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13. Thiruchelvam M, Brockel BJ, Richfield RB, et al. Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson's disease? Brain Res. 2000;873: 225-234.

14. Ling Z, Chang QA, Tong CW, et al. Rotenone potentiates dopamine neuron loss in animals exposed to lipopolysaccharide prenatally. Exp Neurol. 2004; 190:373-383.

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17. Hancock DB, Martin ER, Fujiwara K, et al. NOS2A and the modulating effect of cigarette smoking in Parkinson's disease. Ann Neurol. 2006;60:366-373.