Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the presence, in the brain, of intra-cellular protein inclusions highly enriched in aggregated α-synuclein (αSyn), known as Lewy bodies. The onset of PD is accompanied by a local immune reaction in regions of the brain affected by the inclusions, although the mechanism that leads to pathogenesis is far from clear. It is, however, established that disease onset and progression are characterized by sustained activation of microglia, which is linked to significant dopaminergic neuron loss in the substantia nigra. A recent body of evidence indicates that aggregated or modified αSyn can indeed trigger the activation of microglia, inducing a lethal cascade of neuroinflammation and eventually, neuronal loss, pointing at aggregated and modified forms of αSyn as a primary cause of PD pathogenesis. By releasing toxic factors, or by phagocy-tosing neighbouring cells, activated microglia and astrocytes may form a self-perpetuating cycle for neuronal degeneration. Additional findings suggest a link between αSyn and humoural-mediated mechanisms in PD. In this review, we attempt to recapitulate our current understanding of PD physiopathology focused on αSyn and its links with the immune system, as well as of novel and promising therapeutic avenues for the treatment of PD and of other synucleinopathies.