Background: Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of nigral dopaminergic neurons. In common sporadic but also in rare monogenetic forms of PD caused by mutations in SNCA, an abnormal accumulation of the protein a-Synuclein (a-Syn) has been observed. Given that oligomeric a-Syn can be transmitted in a prion-like way, this phenomenon is likely not restricted to neuronal cells. a-Syn can be 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 to neurodegeneration.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 SNCA triplication mutation, we detected elevated a-Syn protein levels. Moreover, mitochondrial function was compromised in astrocytes from a-Syn mutation carriers. Metabolic studies using an [U-13C]glucose tracer to infer metabolic 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, suggesting that aberrant a-Syn alters astrocytic lipid metabolism.Hypotheses: Therefore, we postulate that: (i) a-Syn pathology in astrocytes disrupts cell metabolism, interfering with gliotransmission and causing downstream deleterious effects in neurons. In turn, a-Syn pathology in neurons elicits astroglial activation that further affects neuronal physiology, initiating a detrimental vicious cycle that is instrumental to the propagation of PD. (ii) Exogenous metabolic intervention or the use of specific inhibitors to compensate for a-Syn-induced disruption of cell metabolism will effectively suppress this astrocytic/neuronal detrimental cycle.Approach: To address our research hypotheses, we will perform in-depth metabolic profiling, mitochondrial function analyses and cell activation assays in astrocytes derived from patients with a-Syn mutations. Moreover, we will use innovative co-culture systems to study the impact of a-Syn released from patient astrocytes on isogenic control neurons. To test if, in turn, neuronal accumulation of a-Syn triggers astroglial activation, we will apply our experimental set-up to isogenic control astrocytes co-cultured with a-Syn-mutant neurons. Finally, we will conduct pathway perturbation and rescue experiments using specific inhibitors or metabolites.Knowledge development: Our study will generate new insights into the effects of a-Syn dysregulation on astrocytic metabolism and the subsequent consequences to neuronal homeostasis. Moreover, we will identify metabolic alterations in astrocytes that are causally linked to the a-Syn-driven pathology in PD. A better understanding of the metabolic dialogue between astrocytes and neurons will provide a new entry point for therapeutic interventions in PD.