Triggering of Inflammasome by Aggregated alpha-Synuclein, an Inflammatory Response in Synucleinopathies

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Another feature is represented by the formation in these cells of inclusions called Lewy bodies (LB), principally constituted by fibrillar a-synuclein (alpha Syn). This protein is considered a key element in the aetiology of a group of neurodegenerative disorders termed synucleinopathies, which include PD, but the cellular and molecular mechanisms involved are not completely clear. It is established that the inflammatory process plays a crucial role in the pathogenesis and/or progression of PD; moreover, it is known that aggregated alpha Syn, released by neurons, activates microglia cells to produce pro-inflammatory mediators, such as IL-1 beta. IL-1b is one of the strongest pro-inflammatory cytokines; it is produced as an inactive mediator, and its maturation and activation requires inflammasome activation. In particular, the NLRP3 inflammasome is activated by a wide variety of stimuli, among which are crystallized and particulate material. In this work, we investigated the possibility that IL-1 beta production, induced by fibrillar alpha Syn, is involved the inflammasome activation. We demonstrated the competence of monomeric and fibrillar alpha Syn to induce synthesis of IL-1 beta, through TLR2 interaction; we found that the secretion of the mature cytokine was a peculiarity of the fibrillated protein. Moreover, we observed that the secretion of IL-1 beta involves NLRP3 inflammasome activation. The latter relies on the phagocytosis of fibrillar alpha Syn, followed by increased ROS production and cathepsin B release into the cytosol. Taken together, our data support the notion that fibrillar alpha Syn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD.