Summary I believe that combining disease gene discovery approaches with in-depth follow-up mechanistic and functional studies is a unique aspect of my research program. Our recent discovery of “human-specific” pathways and phenotypes (compared to mice) in midbrain DA neurons has led us to focus on patient-derived DA neurons to examine the function of PD-linked genes. By employing co-cultures of iPS-derived neurons, microglia and astrocytes, we will examine the interplay of cell-autonomous and no-cell autonomous pathways that lead to dysfunction of midbrain DA neurons in PD. Moreover, we will use innovative technology to simultaneously examine a large number of genetic variants in a pooled iPS approach that has not been possible previously. Finally, our recent discovery of direct contacts between lysosomes and mitochondrial has opened a completely new opportunity to examine inter- and intra-organellar dynamics in neurodegeneration. The R35 award would provide me the time, freedom and stability to be even more adventurous and, as always, follow the most interesting biology to have a high impact on the field.