Etiology

Leonardo Da VinciThe cause of most cases of PD remains unknown. Several pathogenic processes have been implicated in either initiating or contributing to the prolonged and progressive neurodegeneration typically observed in PD patients. Critical unanswered questions include whether certain pathological pathways are primary or secondary to the disease, the contributions of genetic and environmental risk factors, and the impact of compensatory mechanisms on disease progression. Rarely, certain familial forms of PD and related parkinsonism are associated with clear genetic causes (Biskup et al., 2008; Gasser, 2009), while other forms of PD have been linked to specific environmental causes (Jang et al., 2008; Thrash et al., 2007; Langston et al., 1983). However, most instances of 'sporadic' or 'idiopathic' PD likely result from the interactions of multiple factors (de Lau and Breteler, 2006).

Understanding PD pathogenesis is complicated by the great variability in clinical presentation, which points to a variety of potential causes and mechanisms underlying the disease. The growing interest in reassessing how PD is defined (Langston, 2006; Weiner, 2008) and how PD subtypes (Graham et al., 1999; Post et al., 2008) may be recognized is likely to advance both pre-clinical and clinical studies of PD pathogenesis.

An increasing appreciation of both the genetic and environmental factors as well as the underlying pathogenic and compensatory mechanisms involved in PD has enabled the development of pre-clinical research models that can reproduce some of the symptoms and pathological features of human PD. These models have helped identify many of the biological components of cellular pathways altered in PD (Terzioglu and Galter, 2008; Meredith et al., 2008) and highlighted numerous targets for further therapeutic development.