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Pre-formed fibrils of recombinant α-synuclein were injected into the olfactory bulb (OB) of wild-type mice, and spreading was assessed by evaluating the distribution of pathological, phosphorylated α-synuclein. The fibrils were initially taken up by mitral cells in the OB, and after one month, α-synuclein pathology had spread into other regions of the olfactory system that form direct connections with the OB. Between 3 and 12 months, pathology progressed into regions within one-to-two synapses from the OB, suggesting spread along neural tracts. Some olfactory behavior deficits were measurable within 1 month following injection, suggesting pathology-induced dysfunction of neurons in the olfactory system. Intriguingly, pathology induced by mouse α-synuclein fibrils was more widespread than that induced by human α-synuclein, suggesting species-specific differences in structure and/or transmissibility of the fibrils in mouse brains.
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Cell-to-cell transmission of protein aggregates formed by mutant Htt exon 1 was shown to occur between neurons and phagocytic glia in the Drosophila CNS. Numbers of mutant Htt aggregates in olfactory receptor neuron (ORN) axon terminals were regulated by neighboring Draper-dependent phagocytic glial cells. Phagocytosed neuronal aggregates gained access to the glial cytoplasm, evidenced by prion-like conversion of glial cytoplasmic wild-type Htt proteins into an aggregated form. These findings suggest that phagocytic glia can protect against the toxic effects of protein aggregates in neurons but also promote the prion-like spreading of phagocytosed aggregates.
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