Mitochondrial signalling at the interface of genetics and environment in Parkinson’s disease

Parkinson’s disease (PD) is the fastest growing neurodegenerative disorder, lacking neuroprotective treatment options. PD results from an interplay between environmental and genetic factors, explaining why symptoms between mutation carriers vary. Some individuals with PD gene mutations never manifest any signs of the disease - a phenomenon referred to as "reduced penetrance". It remains unknown, which molecular mechanisms impact the penetrance of a given PD-associated mutation. Mitochondria are situated at the interface between genetics and environment. In MitoDefinePD, we aim to demonstrate that mitochondria are central signaling hubs that integrate environmental insults and genetics, thereby defining the penetrance of LRRK2 mutations - the most frequent genetic cause of PD. Applying toxicology analyses to household dust samples as well as omics, imaging and functional studies to iPSC-derived midbrain neurons from controls, manifesting and non-manifesting LRRK2 mutation carriers that were treated with the top exposomics hits, we will unravel how environmental and genetic determinants converge at the level of 1) mitochondrial signaling pathways, 2) mitochondrial DANN integrity and expression, as well as 3) mitochondrial functions. Ultimately, the obtained insights will be used to computationally identify mitochondrial pathways that may serve as drug targets in personalized medicine approaches. Taking a radically different approach than conventional mechanistic studies that typically explore the cellular consequences of mutations, MitoDefinePD can critically shift the scientific paradigm regarding the role of mitochondria in genetic PD. By unequivocally establishing a gene-mitochondria-environment axis, we hope to redefine mitochondria as vectors that mediate gene-environment interactions intra- and intercellularly within and beyond PD. MitoDefinePD will uncover cellular strategies to cope with genetic insults, thereby paving the way for research into novel neuroprotective PD therapies.