Research projects

This section introduces all current and prospective projects of the Molecular & Functional Neurobiology group.

The role of the mitochondrial genome in idiopathic Parkinson’s disease

One of the cellular hallmarks of PD is mitochondrial dysfunction due to respiratory chain complex deficiencies and, hence, disturbance of the neuronal energy metabolism in the dopaminergic neurons of the substantia nigra. However, the molecular pathways involved in respiratory failure and subsequent neurodegeneration remain unknown. Moreover, no treatment preventing or delaying the demise of dopaminergic neurons in PD is currently available. In IPD, neurohistological studies have linked respiratory chain dysfunction to somatic alterations in the mitochondrial DNA (mtDNA). In collaboration with the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, we identified impaired mito-nuclear signalling as the cause of mtDNA disintegration in IPD. To study this phenomenon in a longitudinal fashion, we have now developed an iPSC-based model system of IPD. In patient-derived dopaminergic neurons, we are investigating the mechanisms underlying IPD by exploiting the natural heterogeneity of mitochondrial phenotypes, such as respiratory chain complex I deficiency, and follow the occurrence of somatic mtDNA changes over time. Our study further aims to identify therapeutic targets that have the potential to rescue mtDNA phenotypes thereby preventing neurodegeneration in IPD. This project is funded through the ATTRACT programme of the Luxembourg National Research Fund (FNR).

Grünewald A, Rygiel KA, Hepplewhite PD, Morris CM, Picard M, Turnbull DM. Mitochondrial DNA depletion in respiratory chain-deficient Parkinson disease neurons. Ann Neurol. 2015 Nov 25 [Epub ahead of print] DOI: 10.1002/ana.24571

Exploring the involvement of the Parkinson’s disease-associated protein Parkin in mtDNA maintenance, replication and transcription 

Mutations in Parkin explain up to three quarters of familial PD cases with an early onset of the movement disorder. Regarding the protein’s function, there is strong evidence in the literature that Parkin is involved in the clearance of depolarized mitochondria. However, more recent studies employing iPSC-derived dopaminergic patient neurons raised some doubt as to the physiological relevance of this finding. Interestingly, latest work in neuronal cell lines and an mtDNA “mutator” mouse model suggests that Parkin protects the mitochondrial genome against mutagenic stress via its interaction with the mitochondrial transcription factor A (TFAM). Whether this is also true in human dopaminergic neurons under endogenous conditions currently remains elusive. To address this research question, we are investigating mtDNA integrity, replication and transcription as well as mitochondrial and neuronal function in iPSC-derived neurons from PD patients with Parkin mutations and controls. In these cells, we further intend to study the interaction between Parkin, TFAM and the mtDNA. Finally, we will explore the capacity of wildtype Parkin to rescue mtDNA-associated phenotypes in iPSC-derived neurons with an error-prone mtDNA polymerase gamma. This study will elucidate a novel and potentially more physiologically relevant role of Parkin in the pathogenesis of genetic PD and hence might lead to entirely novel research avenues towards an anti-neurodegenerative treatment in PD.

Patient-derived cortical neurons as a model system to study the disease mechanisms underlying Myoclonus- Dystonia

This project aims to elucidate the mechanisms underlying Myoclonus-dystonia (M-D) - a movement disorder characterized by dystonic features and myoclonic jerks - through the development of a suitable cellular model systems. M-D can be caused by mutations in the ɛ-sarcoglycan (SGCE) gene (Grünewald et al. Hum Mut 2008) which codes for a component of the dystrophin-associated glycoprotein complex (DGC) that links the cytoskeleton with the extracellular matrix. SGCE-associated M-D is autosomal-dominantly inherited with reduced penetrance due to maternal imprinting. Previously it has been shown that SGCE is differentially methylated on CpG dinucleotides in the promoter region, which is a characteristic feature of imprinted genes (Müller et al. Am J Hum Genet 2002). In collaboration with the Institute of Neurogenetics at the University of Lübeck, we assessed the methylation status of the promoter region and the expression ofSGCEduring the generation and neuronal differentiation of induced pluripotent stem cells. These analyses showed faithfulSGCEimprinting iniPSC-derived cortical neurons from M-D patients highlighting the suitability of these cells as disease model (Grütz et al. Sci Rep 2017). As a next step, we now want to use our endogenous M-D model to study the impact of different mutations in ɛ-sarcoglycan on the cellular localization of the protein and its ability to interact with other components of the DGC. These experiments will help to characterize the mechanisms leading to M-D.

Markers and mechanisms of reduced penetrance in LRRK2 mutation carriers of Parkinson’s Disease

While known PD genes are commonly grouped by mode of transmission as ‘dominant’ or ‘recessive’, actual patterns of inheritance and boundaries between dominant and recessive modes are much less well defined than previously thought. Although individuals may harbour an identical mutation for instance in the LRRK2 gene, their disease manifestation and age at onset may vary considerably. So far, only few factors have emerged, which impact on disease penetrance or constitute signs of advanced progression in LRRK2-PD. In this study, we are using a large set of fibroblasts from affected and unaffected individuals with the common G2019S mutation in LRRK2 to validate the specificity of known penetrance markers (such as LRRK2 autophosphorylation). Moreover, we aim to identify novel cellular signals that allow a reliable prediction of PD onset in non-manifesting carriers. To further explore how central to the disease mechanism these markers are, we are developing iPSC-based neuronal models of LRRK2 PD penetrance. The research project is part of a collaborative effort between the Universities of Lübeck, Luxembourg, Kiel, Rostock, British Columbia and the European Academy Bolzano. Within the framework of the Research Unit “ProtectMove” (, which is co-funded by the FNR and the DFG, the involved partners explore molecular mechanisms accelerating or delaying disease onset in various movement disorders.

Mitochondrial DNA as a trigger of neuroinflammation in Parkinson’s disease

Recent studies suggest that mitochondria are key regulators of neuroinflammation in PD. Particularly, the release of mitochondrial DAMPs (damage-associated molecular patterns), which might include mitochondrial-derived ROS, proteins, lipids and mtDNA, have been shown to elicit innate immune responses. In a PD context, the release of these mitochondrial DAMPs seem to be secondary to mtDNA instability or mitochondrial dysfunction. However, the signalling cascade involved in this inflammatory process and the real extension to which it contributes to cell death and disease propagation in PD is unclear. To answer these questions, we are studying mtDNA levels, dynamics (transcription and replication) and stability (deletions) in distinct familial and idiopathic PD models, which include neural stem cells and dopaminergic neurons differentiated from patient-derived iPSCs and genetically modified neuronal cell lines (SH-SY5Y). We are also investigating the consequences of mtDNA release into the cytosolic and extracellular milieu and trying to identify the molecular pathways that link this release to neuroinflammation. Furthermore, glial cells will be used to test the functional capacity of neuronal-derived mtDNA to elicit immune responses in such cell types. Our approach will help clarifying the processes leading to inflammation in PD and identifying suitable targets for mitochondria-targeted therapy.