Contribution of Astrocyte Metabolism to Synucleinopathy in Parkinson’s disease.

Background: Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss ofnigral dopaminergic neurons. In common sporadic but also in rare monogenetic forms of PD caused by mutationsin SNCA, an abnormal accumulation of the protein α-Synuclein (α-Syn) has been observed. Given that oligomericα-Syn can be transmitted in a prion-like way, this phenomenon is likely not restricted to neuronal cells. α-Syn canbe engulfed by astrocytes, which are providing structural as well as metabolic support for neurons. Interestingly,overexpression of mutant SNCA in mice caused astrogliosis and induced an inflammatory response, which led toneurodegeneration.
Own contribution to the state-of-the art: We have developed an improved protocol for the generation of pure, non-activated astrocyte cultures from induced pluripotent stem cells (iPSCs). In astrocytes from patients with an SNCAtriplication mutation, we detected elevated α-Syn protein levels. Moreover, mitochondrial function wascompromised in astrocytes from α-Syn mutation carriers. Metabolic studies using an [U-13C]glucose tracer to infermetabolic fluxes revealed striking differences in the labelling pattern of metabolites related to the Krebs cycle.Specifically, we observed an increased flux of glucose-derived carbon into the acetate and lipid pool, suggestingthat aberrant α-Syn alters astrocytic lipid metabolism.Hypotheses: Therefore, we postulate that: (i) α-Syn pathology in astrocytes disrupts cell metabolism, interferingwith gliotransmission and causing downstream deleterious effects in neurons. In turn, α-Syn pathology in neuronselicits astroglial activation that further affects neuronal physiology, initiating a detrimental vicious cycle that isinstrumental to the propagation of PD. (ii) Exogenous metabolic intervention or the use of specific inhibitors tocompensate for α-Syn-induced disruption of cell metabolism will effectively suppress this astrocytic/neuronaldetrimental cycle.Approach: To address our research hypotheses, we will perform in-depth metabolic profiling, mitochondrial functionanalyses and cell activation assays in astrocytes derived from patients with α-Syn mutations. Moreover, we will useinnovative co-culture systems to study the impact of α-Syn released from patient astrocytes on isogenic controlneurons. To test if, in turn, neuronal accumulation of α-Syn triggers astroglial activation, we will apply ourexperimental set-up to isogenic control astrocytes co-cultured with α-Syn-mutant neurons. Finally, we will conductpathway perturbation and rescue experiments using specific inhibitors or metabolites.Knowledge development: Our study will generate new insights into the effects of α-Syn dysregulation on astrocyticmetabolism and the subsequent consequences to neuronal homeostasis. Moreover, we will identify metabolicalterations in astrocytes that are causally linked to the α-Syn-driven pathology in PD. A better understanding of themetabolic dialogue between astrocytes and neurons will provide a new entry point for therapeutic interventions inPD.