The common neuropathological hallmark of synucleinopathies is the deposition of aggregated α-synuclein. The spectrum of synucleinopathies ranges from Parkinson’s disease (PD) to dementia with Lewy bodies (DLB). High neuronal toxicity was shown for oligomeric conformations of α-synuclein, whereas fibrillary conformations have been considered less detrimental. Previous work identified an artificial of α-synuclein, that is almost exclusively present in the oligomeric state and thus allows to specifically investigate the toxic conformation. Our current focus is neurite integrity in human PD models and the impact of neuroinflammation in PD.
To understand the contribution of α-synuclein oligomers to neurite pathology in human neurons we investigate axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells. We are specifically interested in how increased levels of α-synuclein oligomers associate with disrupted axonal integrity and, what is the critical species triggering early axonal dysfunction in synucleinopathy.
Moreover, we are interested in the impact of neuroinflammation in PD. While the role of local central nervous system (CNS) innate immune cells, and specifically activation of microglia and pro-inflammatory cytokine release in neurodegeneration have been investigated in detail, a potential influence of adaptive immune cells and specifically the role of lymphocytes in synucleinopathies, has just started to attract growing attention. We focused on disease-specific alterations of lymphocytes in the circulating blood and investigated CNS-infiltration of lymphocytes in a mouse model for synucleinopathies. We found decreased amounts of α-synuclein aggregates in the absence of T- and B-cells. When T-lymphocytes are present, microglia phagocytoses less α-synuclein, which aggravates synucleinopathy (Sommer et al., Journal of Neuroinflammation 2016). To dissect the role of adaptive immune cells in sporadic PD in absence of innate immune cells, we switched to a human autologous co-culture of patients' neurons and T- lymphocytes and are currently investigating the direct impact of T-lymphocytes on neurons in PD patients in an autologous co-culture system.
Fred H. Gage