Abstract
The precise etiology for idiopathic Parkinson’s disease (PD) is currently unknown; however several lines of converging evidence exist to suggest a central role of pathlogic aggregation of alpha-synuclein as a driving force underlying mechanisms of PD neurodegeneration. First, pathogenic missense mutations1 or gene multiplications2 of the alpha-synuclein gene (SCNA) result in an increased propensity for alpha-suniclein to fibrillize in vitro3 and clinically manefest as early-onset PD with typical Lewy pathology (LP) composed chiefly of insoluble amyloid fibrils formed by pathologically altered alpha-syunclein proteins at autopsy.4 Comparisons of large numbers of PD cases at autopsy demonstrate a sequential non-random progression of LP from the lower brainstem into limbic and neocortical regions in the majority of PD patients.5 This progression of LP into neocortical areas appears to be the strongest neuropathological correlate of dementia in PD,6–8 further reinforcing the importance of alpha-synuclein misfolding and aggregation into LP in the neurodegenerative process. Finally, recent work in cell9, 10 and animal11, 12 models of PD demonstrated that pathological alpha-synuclein proteins may spread from neuron-to-neuron to induce LP as well as neurodegeneration. Furthermore, in animal models, this process recapitulates clinical and pathological phenotypes of PD, thereby mirroring the proposed staging systems5, 13 of LP in human disease. Indeed, alpha-synuclein fibrils alone, appear to be capable of transmission of LP within an animal.11, 12 Despite these similarities to PrPsc neuron-to-neuron transmission in the spongiform encephalopathies,14 there is currently no data to suggest humans15 or non-human-primates16 exposed to pathogenic alpha-synuclein from brain tissue of PD patients develop clinical PD. Thus, the apparent lack of transmission between individuals is in sharp contrast to human prion disease.
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