Internalized α-synuclein fibrils become truncated and resist degradation in neurons while glial cells rapidly degrade α-synuclein fibrils.
Parkinsons disease (PD) and other -synucleinopathies are characterized by the intracellular aggregates of -synuclein (S) believed to spread via the cell-to-cell transmission. To understand the contributions of various brain cells to the spreading of S pathology, we examined the metabolism of S aggregates in neuronal and glial cells. In neurons, while the full-length S rapidly disappeared following S PFF uptake, truncated S accumulated with a half-life of days rather than hours. Epitope mapping and fractionation studies indicate that S fibrils internalized by neurons was truncated at the C-terminal region and remained insoluble. In contrast, microglia and astrocytes rapidly metabolized S fibrils as the half-lives of S fibrils in these glial cells were <6 hours. Differential uptake and processing of S fibrils by neurons and glia was recapitulated in vivo where injection of fluorescently labeled S fibrils initially accumulated in glial cells followed by rapid clearance while neurons stably accumulated S fibrils at slower rate. Immunolocalization and subcellular fractionation studies show that internalized S PFF is initially localized to endosomes followed by lysosomes. The lysosome is largely responsible for the degradation of internalized S PFF as the inhibition of lysosomal function leads to the stabilization of S in all cell types. Significantly, S PFF causes lysosomal dysfunction in neurons. In summary, we show that neurons are inefficient in metabolizing internalized S aggregates, partially because S aggregates cause lysosomal dysfunction, potentially generating aggregation-prone truncated S. In contrast, glial cells may protect neurons from S aggregates by rapidly clearing S aggregates.