Glial handling of alpha-synuclein seeds: uptake, degradation and redistribution in pathological propagation

α-synuclein (αS) aggregation and propagation are central features of Parkinson’s disease pathology. Preformed fibril (PFF) models have shown that extracellular αS aggregates can enter neurons and seed aggregation of endogenous αS. Within the brain, these seeds also encounter microglia and astrocytes, which efficiently internalise fibrillar αS and can influence its subsequent fate. This review examines the mechanisms through which glial cells take up, process, degrade and redistribute extracellular αS seeds. When lysosomal trafficking and degradation are effective, glia can act as a sink for seed-competent αS and restrict neuronal seeding and propagation. In contrast, lysosomal dysfunction, incomplete proteolysis or excessive aggregate burden can promote persistence, modification and redistribution of seed-competent αS, including through extracellular vesicles and intercellular transfer. Evidence from microglial and astrocytic models therefore indicates that the outcome of glial uptake depends on the balance between internalisation, intracellular processing and subsequent release. Differences in αS conformation, fibril preparation, inflammatory state, genetic background and experimental model may further explain the apparently protective and pathogenic effects of glia reported across different studies. Understanding the factors that determine whether glial uptake results in productive clearance or continued propagation may identify therapeutic strategies that enhance the removal of pathogenic αS without broadly suppressing glial function.