Elucidation of cytotoxicity of α-Synuclein fibrils on immune cells

Progressive aggregation of α-synuclein (α-Syn), a small cytosolic protein involved in cell vesicle trafficking, in the midbrain, hypothalamus, and thalamus is linked to Parkinson's disease (PD). Amyloid oligomers and fibrils formed as a result of such aggregation are highly toxic to neurons. However, it remains unclear whether amyloid-induced toxicity of neurons is the primary mechanism of the progressive neurodegeneration observed upon PD. In the current study, we investigated cytotoxicity exerted by α-Syn fibrils formed in the lipid-free environment, as well as in the presence of two phospholipids, on macrophages, dendritic cells, and microglia. We found that α-Syn fibrils are far more toxic to dendritic cells and microglia compared to neurons. We also observe low toxicity levels of such amyloids to macrophages. Real-time polymerase chain reaction (RT-PCR) results suggest that toxicity of amyloids aggregates is linked to the levels of autophagy in cells. These results suggest that a strong impairment of the immune system in the brain may be the first stop of neurodegenerative processes that are taking place upon the onset of PD.