How does parkinson's disease begin? Perspectives on neuroanatomical pathways, prions, and histology

Parkinson's disease (PD) is a multisystem disorder with involvement of the peripheral nervous system. Misfolding and aggregation of α‐synuclein is central to the pathogenesis of PD, and it has been postulated that the disease may originate in olfactory and gastrointestinal nerve terminals. The prion‐like behavior of α‐synuclein has been convincingly demonstrated in vitro and in animal models of PD. Lewy‐type pathology have been detected in peripheral organs many years prior to PD diagnosis, and 2 independent studies have now suggested that truncal vagotomy may be protective against the disorder. Other lines of evidence are difficult to reconcile with a peripheral onset of PD, most importantly the relative scarcity of post mortem cases with isolated gastrointestinal α‐synuclein pathology without concomitant CNS pathology. This Scientific Perspectives article revisits some important topics with implications for the dual‐hit hypothesis. An account of the neuroanatomical pathways necessary for stereotypical α‐synuclein spreading is presented. Parallels to the existing knowledge on true prion disorders, including Creutzfeld‐Jakob disease, are examined. Finally, the vagotomy studies and the somewhat inconsistent findings in the growing literature on peripheral α‐synuclein pathology are discussed. It is concluded that the dual‐hit hypothesis remains a potential explanation for PD pathogenesis, but several issues need to be resolved before more firm conclusions can be drawn. © 2017 International Parkinson and Movement Disorder Society