Assessment of far-reaching spread of Parkinson's pathology in Parkinson's disease

Recently, we have shown that transplanted fetal dopamine-producing neurons develop Lewy body pathology more than 10 years after surgery in patients with Parkinson's disease (PD), suggesting the spread of disease from the host environment to the transplanted cells. Evidence also shows that the progression of Lewy body pathology occurs in anatomically interconnected nerves and that these susceptible neurons are not neurotransmitter-dependent, suggesting long-distance transport of the diseased protein, alpha-synuclein (a-syn) and its aggregates, Lewy bodies and Lewy neuron protrusions. However, these hypotheses have not yet been tested. Our hypothesis is that a-syn oligomers and fibrils are central to the long-distance spread of Lewy body pathology. Using both in vitro and in vivo models, in combination with imaging techniques to study living cells and biochemical processes, we will address two key questions about how PS can spread: (i) Whether, and if so how, oligomeric and fibrillar a-syn are transported via antero- and/or retrograde transport within the neuron, and (ii) Whether, and how, these a-syn species can be transported between neurons. Successful demonstration of the patterns and underlying mechanisms of long-range spread of Lewy body pathology in nerves will open new avenues to identify novel targets to intervene in PS pathogenesis and slow, or stop, the progression of the disease.