α-Synuclein is implicated in central and peripheral neuropathology in both familial and sporadic forms of Parkinson disease. Although the mechanisms underlying α-synuclein toxicity are unknown, targeting the protein directly is a heavily investigated therapeutic avenue. One such approach, undertaken by Jankovic et al in this issue of JAMA Neurology,1 uses passive immunization (PRX002) to clear the presumptive pathological aggregated forms of the protein from the extracellular environment. Although this well-designed phase 1b trial successfully reached its predetermined end points, the observation of a marked reduction in serum α-synuclein (which was the rationale for this trial and others like it2) is based on heavily debated preclinical research in a field that is lacking animal models with strong face validity. The entire premise of the current PRX002 clinical trial is based on the notion that extracellular or aggregated α-synuclein is capable of cell-to-cell transmission and thus capable of propagating the disease process and resultant neurodegeneration. This phenomenon is documented to occur in model systems,3 but whether it occurs in humans is, to our knowledge, completely unknown at this point. This hypothesis could potentially explain the temporal progression noted in various staging schema of Parkinson disease (which are controversial),4,5 but little direct clinical evidence that directly proves this prion hypothesis of Parkinson disease exists. Indeed, the rationale for this approach is largely based on animal models6,7 where supraphysiological levels of ectopic α-synuclein are associated with measurable extracellular aggregated content and subsequent toxicity. The question remains: to what extent does this process reflect the role of α-synuclein in the causal mechanisms of Parkinson disease?
Manfredsson FP, Tansey MG, Golde TE. Challenges in Passive Immunization Strategies to Treat Parkinson Disease. JAMA Neurol. Published online June 18, 2018. doi:10.1001/jamaneurol.2018.0346
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