The role of the mitochondrial genome in neuroinflammation in Parkinson's Disease
Katja Badanjak, PhD supervisor: Anne Grünewald
The project aims to characterise critical changes in mitochondria with respect to disease development and potential compensatory mechanisms. The molecular and functional neurobiology group recently established quantitative immunofluorescence as an assay to investigate the relationship of several mitochondrial target proteins in single neurons. This technique has been used in conjunction with laser-capture microdissection and real-time PCR mtDNA analysis. Beyond single-cell methods, the group has expertise in studying mitochondrial function and morphology using patient-derived cellular systems. Mitochondria are key players in cellular metabolism and apoptotic signalling, thereby deciding cell fate in Parkinson’s disease and in cancer.
Preliminary experiments in single dopaminergic neurons from post-mortem midbrain sections suggest TFAM-mediated mtDNA depletion as a critical step in the development of respiratory chain dysfunction in Parkinson’s disease. In a recent article, mtDNA stress due to TFAM deficiency was shown to trigger antiviral signalling. Accordingly, loss of TFAM packaging of the mitochondrial genome promotes its transition into the cytosol where mtDNA fragments initiate type I interferon responses. Further, the authors reported that mtDNA stress could be induced by herpes viruses, which have also been associated with Parkinson’s disease. Based on these findings, the first aim of the proposed project is to elucidate the role of TFAM deficiency-mediated mtDNA stress in the detrimental cascade leading to neuroinflammation and -degeneration in Parkinson’s disease. Secondly, we intend to establish whether herpes virus infections contribute to mtDNA depletion and mitochondrial dysfunction in dopaminergic neurons thereby accelerating the transition from a healthy to pathological cellular state. Experiments will include proteomic and real-time PCR mtDNA analyses in single post-mortem substantia nigra neurons from patients and age-matched controls with and without HSV-1. Furthermore, the project will also use the single-cell omics platforms. In addition, non-infected patient-derived iPSC-neurons will be challenged with HSV-1 to study the impact of an infection on the cellular localisation of TFAM and the mitochondrial genome as well as on general mitochondrial and neuronal function.