Neuron-to-neuron propagation of ?-synuclein (?-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the stereotypical progression pattern of ?-syn neuropathology. This postulate suggests that aggregated ?-syn transfers from one neuron to another where it seeds further ?-syn aggregation. However, it is not known how microglia influence this process, and how specific microglia activation states that occur upon inflammation affect ?-syn transfer. To fill this gap i knowledge we developed a unique mouse model that allows us to monitor ?-syn prion-like propagation between neurons. Our in vivo paradigm involves transplantation of embryonic midbrain neurons into the striatum of a mouse overexpressing human ?- syn and allows the manipulation of microglia (i.e. ablation or specific activation). In this novel model, the presence of human ?-syn within the grafted mouse cells (initially devoid of human ?-syn) is used as a read-out for ?-syn transfer. Based on our preliminary data we hypothesize that under normal conditions, microglia take up ?-syn from the extracellular space, resulting in reduced ?-syn transfer from neuron to neuron. We also hypothesize that ?-syn accumulates in microglia following lipopolysaccharide treatment, as lipopolysaccharide -activated microglia have reduced proteolytic capacity whereas Interleukin 4-induced microglia effectively reduce the pool of extracellular ?-syn, and thereby mitigate ?-syn transfer from neuron to neuron.
Two specific aims will be pursued to test this hypothesis: 1) Determine how the absence of microglia affects neuron-to-neuron transfer of ?-syn; and 2) Determine how the presence of lipopolysaccharide-induced vs Interleukin 4-induced activated microglia affects the rate of neuron-to-neuron transfer of ?-syn. First, we will monitor if the absence of microglia results in a different degre of ?-syn cell-to-cell transfer using our unique in vivo model of cell-to-cell transfer. Second, we wil assess the transfer of ?-syn into grafted neurons in the context of distinct microglial phenotypes lipopolysaccharide or Interleukin 4 injection will be used to stimulate these differential phenotypes. Our approach is innovative because it allows us to assess the interaction between two factors (inflammation and ?-syn propagation) both considered to play key roles in PD pathogenesis in a single animal model, and we can define outcomes using unbiased, automated and quantitative measures of neuropathology. We predict that the absence of microglia will translate to increased neuron-to-neuron transfer of ?-syn and that the nature of microglial activation will affect the accumulation of ?-syn within microglia. Ultimately, the proposed research will result in an innovative and valid model of ?-syn pathology propagation with the potential to facilitate the development of disease-modifying therapies based on treatments that modulate inflammation.
The proposed research is relevant to public health because understanding a key mechanism of pathology in Parkinson's disease (PD) is expected to allow the identification of interventions that can be developed into new clinical therapies that improve the quality of life of people with PD. The proposed research is relevant to the missions of NIH and NINDS 1 because it aims to generate tools that catalyze the development of therapies that stop PD progression and thereby reduce the financial burden and significant morbidity associated with advanced PD.
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