Parkinson's disease (PD) is a common age-related neurodegenerative disease characterized by movement disorders. The hallmark pathological lesions of PD are the formation of Lewy pathology in selected populations of neurons throughout the nervous system. Braak and his colleagues created a staging system for PD describing the connection between Lewy pathology and disease severity. They proposed that Lewy pathology might be initially triggered by exogenous pathogens tar-getting the enteric or olfactory nervous system, then spread in a prion-like propagation manner from the peripheral nerves to the lower brainstem and midbrain, before final-ly reaching higher cortical structures, causing a sequen-tial occurrence of the non-motor and motor symptoms, depending on the lesioned neurons. However, emerging evidence also supports a functional threshold hypothesis proposed by Engelender and Isacson in which Lewy pa-thology may occur parallelly in the central and peripher-al nervous systems and the symptoms only begin when the functional reserve of the affected neurons (and their connecting brain regions) is unable to allow for network compensation. Consequently, early symptoms of PD reflect the loss of function in the least compensated systems, such as the enteric and olfactory nervous systems, rather than the spread of Lewy pathology from the peripheral to the cen-tral nervous systems. The current review article provides a comprehensive overview of the evidence supporting a merged mechanism that the neurodegeneration in PD hap-pens to those neurons that are not only intrinsically vul-nerable but also affected by the spread of Lewy pathology.