α-Synuclein uptake, accumulation, and inflammatory responses in Parkinson’s disease

Abstract

The misfolded protein α-synuclein is integral to the pathogenesis of Parkinson’s disease, leading to the death of dopaminergic neurons in the substantia nigra and resulting in the development of motor symptoms. Parkinson’s disease is usually considered a disease of neurons, however, non-neuronal cells could also be affected but have not been extensively studied. In this thesis, novel effects of α-synuclein in non-neuronal cells were investigated using human olfactory bulbs and in vitro cultures of pericytes and microglia derived from the human brain. Non-neuronal cells – pericytes, astrocytes and microglia contained α-synuclein in the Parkinson’s disease human olfactory bulb in similar numbers to neuronal cells. These findings were the basis for investigating the responses of primary human brain pericytes and microglia in vitro exposed to recombinant α-synuclein. This thesis demonstrates that α-synuclein does not induce inflammation in primary human brain pericytes and microglia except when it is heavily contaminated with bacterial endotoxins. Endotoxin-free α-synuclein did not induce inflammation in these cells. Additionally, primary human brain pericytes efficiently take up α-synuclein from the extracellular culture media, however, control and Parkinson’s disease autopsy post-mortem cells did not efficiently degrade the α-synuclein protein. Lastly, α-synuclein treatment alone did not induce cell death in primary human brain pericytes, however, treatment of pericytes with an additional stressor led to the induction of reactive oxygen species and subsequent cell death. These data suggest that non-neuronal cells are important in the pathogenesis of Parkinson’s disease and further understanding how they react to α-synuclein could provide new therapeutic approaches.