Complement as driver of neuroinflammation and -degeneration in Parkinson‘s disease

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Heterozygous mutations in the β-glucocerebrosidase (GBA) gene have been identified as one of the strongest risk factors for Parkinson’s disease, a movement disorder that is pathologically characterized by the degeneration of dopaminergic neurons. Homozygous mutations of GBA are responsible for Gaucher’s disease, which is the most prevalent lysosomal storage disorder, characterized by decreased activity of the encoded lysosomal enzyme glucocerebrosidase and subsequent accumulation of its substrate glucosylceramide (GC) in several organs including the brain. Recently, autoantibody generation against GC was shown in Gaucher’s disease patients that form GC-specific immune complexes. Such complexes activated the complement system resulting in C5a generation, which triggered the activation of its cognate C5a receptor 1 (C5aR1) on immune cells in Gaucher-prone mice and patients. Several observations point also to a significant contribution of the immune system in the etiology of Parkinson’s disease, however, the mechanisms driving the activation of immune cells remains unclear. The overall hypothesis underlying this application is that reduced glucocerebrosidase activity leads to complement activation and subsequent complement-driven microglia activation in the brain of patients with GBA-associated parkinsonism. To address this hypothesis, we will determine levels of complement factors C3, C5 and their cleavage fragments, C3a and C5a, in postmortem brain and cerebrospinal fluid samples from patients carrying GBA mutations. Further, we will generate a neuron-microglia co-culture disease model from patient-derived induced pluripotent stem cells (iPSC) (Objective 1). We will assess the activation of microglia and the autonomous production of complement factors C3 and C5, and cleavage into C3a and C5a in such cells to define the level of complement activation comparing patient vs. control cells (Objective 2). Moreover, we will determine the direct neuroprotective effect of a genetic knockout or pharmacological inhibition of C5aR1 in this model. To gain mechanistic insight into GBA-linked neuroinflammatory processes we will perform single-cell expression profiling of neuron-microglia co-cultures (Objective 3). The project builds on the extensive expertise of the applicants in iPSC technology and neuroscience as well as complement and inflammation research. Elucidating the mechanisms leading to neuroinflammation in parkinsonism might be of great therapeutic relevance in the future.