[Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease].

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).