PR001536 (Project)

Description:Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors with largely unknown etiology. Prominent pathological culprits include metabolic as well as mitochondrial alterations which have been identified in patients, however, their relevance at different stages of disease progression or their connection remains largely elusive. Here, human iPSCs from late-onset sPD patients were used for disease modeling. Following long-term in vitro cultivation, exclusively neural cells derived from sPD patients developed reduced mitochondrial respiration and glucose consumption reflecting an sPD-specific state of hypometabolism. A multilayered omics analysis based on transcriptomics, proteomics, and metabolomics allowed us to identify the citric acid cycle as being the bottleneck in sPD metabolism. A 13C metabolic flux analysis further unraveled the a-ketoglutarate dehydrogenase complex as being central for a reduced flux through the citric acid cycle. This resulted in a substrate availability problem for the electron transport chain and thus reduced mitochondrial oxygen consumption and ATP production. Notably, these alterations in cellular metabolism were evoked by altered SHH signal transduction due to dysfunctional primary cilia. Upon inhibiting the enhanced SHH signal transduction in sPD, glucose uptake and the activity of the a-ketoglutarate dehydrogenase complex could be restored. Thus, inhibiting overactive SHH signaling may be a potential neuroprotective therapy during the early stages of sPD.