**Etiology and Pathogenesis of Parkinson's Disease**

Taku Hatano and Nobutaka Hattori

*Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan* 

### **1. Introduction**

The pathological hallmarks of Parkinson's disease (PD) are marked loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), which causes dopamine depletion in the striatum, and the presence of intracytoplasmic inclusions known as Lewy bodies in the remaining cells. It remains unclear why dopaminergic neuronal cell death and Lewy body formation occur in PD. The pathological changes in PD are seen not only in the SNc but also in the locus coeruleus, pedunculo pontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, parasympathetic as well as sympathetic post-ganglionic neurons, Mynert nucleus, and the cerebral cortex (Braak et al. 2003). Widespread neuropathology in the brainstem and cortical regions are responsible for various motor and non-motor symptoms of PD. Although dopamine replacement therapy improves the functional prognosis of PD, there is currently no treatment that prevents the progression of this disease.

Previous studies provided possible evidence that the pathogenesis of PD involves complex interactions between environmental and multiple genetic factors. Exposure to the environmental toxin MPTP was identified as one cause of parkinsonism in 1983 (Langston & Ballard 1983). In addition to MPTP, other environmental toxins, such as the herbicide paraquat and the pesticide rotenone have been shown to contribute to dopaminergic neuronal cell loss and parkinsonism. In contrast, cigarette smoking, caffeine use, and high normal plasma urate levels are associated with lower risk of PD (Hernan et al. 2002). Recently, Braak and coworkers proposed the "Dual Hit" theory, which postulated an unknown pathogen accesses the brain through two pathways, the nose and the gut (Hawkes et al. 2007). Subsequently, a prion-like mechanism might contribute to the propagation of αsynuclein from the peripheral nerve to the central nervous system (Angot et al. 2010).

Approximately 5% of patients with clinical features of PD have clear familial etiology. Therefore, genetic factors clearly contribute to the pathogenesis of PD. Over the decade, more than 16 loci and 11 causative genes have been identified, and many studies have shed light on their implication in, not only monogenic, but also sporadic forms of PD. Recent studies revealed that PD-associated genes play important roles in cellular functions, such as mitochondrial functions, the ubiquitin-proteasomal system, autophagy-lysosomal pathway, and membrane trafficking (Hatano et al. 2009). In this chapter, we review the investigations of environmental and genetic factors of PD (Figure 1).

Etiology and Pathogenesis of Parkinson's Disease 3

transporter, and therefore exhibits selective toxicity to dopaminergic neurons. Furthermore, MPP+ accumulates in mitochondria, where it inhibits the mitochondrial electron transport chain component complex I (Przedborski & Vila 2003). Mizuno et al reported that MPP+ inhibited the α-ketoglutarate dehydrogenase complex of the mitochondrial tricarboxylic acid cycle, which synthesizes succinate from α−ketoglutarate (Mizuno et al. 1987). In SNc of sporadic PD subjects, decreased activity and protein levels of complex I have also been reported (Schapira et al. 1989). Thus biochemical changes in dopaminergic neuronal degeneration in sporadic PD were essentially similar to those of subjects exposed to MPTP.

Epidemiological studies have suggested the association between PD and exposure of pesticides such as rotenone and paraquat. Rotenone is a potent and high-affinity specific inhibitor of complex I. In rodents, continuous infusion of these toxic agents induced dopaminergic neuronal cell death and inclusion bodies, which were similar to Lewy bodies in PD patients (Betarbet et al. 2000). Therefore, both MPTP and rotenone disrupt mitochondrial function and play important roles in the nigral cell degeneration in PD. Paraquat, which is a member of a chemical class known as bipyridyl derivatives, is one of the most commonly used pesticides, and leads to oxidative and nitrative stress (Berry et al.). The chemical structure of paraquat is similar to MPP+. Epidemiologic studies implicate the association between exposure to this toxin and the development of PD. Interestingly, recent studies revealed that exposure to a combination of paraquat and maneb, which is also widely used as an agricultural pesticide, exacerbate dopaminergic degeneration in the rodent model and cause an increased incidence of PD in humans (Costello et al. 2009). In this context, exposure to a combination of several toxins could lead to greater risk of

Smokers and coffee drinkers have been associated with a lower risk of PD in several epidemiological studies. Hernan et al. conducted a meta-analytic review for the association between caffeine intake, smoking, and the risk of PD. Interestingly the cigarette smokers had 60% lower risk for the development of PD than people without a history of smoking (Hernan et al. 2002). Some experiments suggested that chronic nicotine treatment could have protective effects against the nigrostriatal neuronal cell death in MPTP-treated animal models. Several studies revealed that cigarette smoking inhibited monoamine oxidase (MAO) activity and nicotine stimulated dopamine release. As a result, cigarette smoking may suppress free radical generation via MAO-B-associated metabolism of dopamine, and be able to protect against dopaminergic cell death (Miller et al. 2007). Similar to cigarette smoking, coffee drinking could result in a 30% decreased risk of PD compared with non-coffee drinkers (Hernan et al. 2002). Chen et al reported that caffeine had similar effects as A2A antagonists, and attenuated MPTP toxicity via A2A

Braak and colleagues proposed neuropathological staging in PD. They reported that the dorsal motor nucleus of the glossopharyngeal and vagal nerves and the anterior olfactory nucleus were initially affected, and subsequently the substantia nigra and locus coeruleus

**2.2 Pesticides** 

developing PD than a single toxin.

receptor blockade (Chen et al. 2001).

**2.4 Disease process and dual hit theory** 

**2.3 Caffeine, cigarette** 

Fig. 1. Although the etiology of Parkinson disease (PD) remains unknown, 5-10% of patients have clear familial etiology, which show a classical recessive or dominant Mendelian mode of inheritance. On the other hand, MPTP or a combination of maneb and paraquat are environmental risk factors for PD. Several PD-related genetic factors (e.g., SNPs in αsynuclein) have been discovered, and the interaction between genetic and environmental factors might contribute to sporadic PD.
