Fitzgerald Lab

The role of PINK1 in an iPSC-derived neuronal model of Parkinson’s disease

Anna Schaedler, Christine Bus (Alumni)

We are currently investigating the role of the Parkinson’s disease kinase PINK1 in human dopaminergic neurons derived from iPSCs and using gene editing technology to generate isogenic controls. With several established readouts to assess mitochondrial function following different stress conditions, we were able to identify distinct mitochondrial phenotypes, which suggest a role for PINK1 in mitochondrial quality control. Using these PINK1 deficient models and their isogenic controls we will now look for genetic and pharmacological modifiers to apply novel neuroprotective strategies.

Max Mattheuer

Mutations in the mitochondrial PTEN-induced putative kinase 1 (PINK1) are the second most common cause of recessive inherited Parkinson´s disease. The mechanism by which the loss of function mutation of PINK1 leads to the death of dopaminergic neurons in the mid brain remains elusive. Working with an iPSC derived model of dopaminergic neurons deficient in PINK1, we aim to gain further insights into the underlying mechanisms. In PINK1 knock out dopamine neurons no classical mitophagy after mitochondrial membrane depolarization was observed, while levels of autophagy and ROS production remained unchanged. The goal of the project is to find potential mechanisms of mitochondrial quality control/recycling in PINK1 knock out dopamine neurons in vitro.

The role of Miro1 in mitochondrial quality control

Lisa Schwarz

Mitochondria play a crucial role in several cellular mechanisms including energy supply, calcium homeostasis and apoptosis. While the matrix and mitochondrial inner membrane are well characterized, little is known about the mitochondrial outer membrane (MOM). The German Research Council research training group (RTG) MOMbrane aims to close this gap by to investigating the various functions of the MOM as well as its structure, regulation and biogenesis. The MOMbrane includes ten PhD students in different institutes in Tübingen, each focusing on a different aspect of the MOM. The project is carried out in collaboration with partner labs of the Weizmann institute in Rehovot (Israel).

Miro1 is located at the MOM and known to be responsible for mitochondrial transport. As part of the MOMbrane RTG, we aim to elucidate the function of Miro1 in mitochondrial turnover, metabolism, calcium signaling. It is known that one of the pathological hallmarks of Parkinson’s disease is altered mitochondrial function. We aim to better understand the biological roles of Miro1 and also its relevance to Parkinson’s disease by studying relevant disease models. To achieve this knowledge, we are introducing disease-associated and functional Miro1 variants in Miro1 in human induced pluripotent stem cells (iPSCs) using gene editing. Healthy and edited iPSCs can then be differentiated into other cell types including neurons.

The role of the endosomal-lysosomal system in atypical Parkinson’s disease/Corticobasal syndrome

Katharina Stegen (Alumni)

Dysfunction of the endosomal-lysosomal system is a phenomenon that traverses many neurodegenerative diseases including Alzheimer’s diseases, Parkinson’s disease and other rarer neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal syndrome/degeneration (CBS/CBD). The endosomal lysosomal system is formed and driven by changes in pH and therefore the ion exchangers that reside in the membranous compartments of the endosomal lumen are critical for correct pH regulation. These exchangers are so crucial that major defects in them often cause severe mental retardation from birth. We are investigating defects that instead confer susceptibility to develop neurodegenerative diseases in later life. We are also investigating aspects of cellular trafficking involving the endosomal-lysosomal system and autophagy that could be involved in sporadic Parkinson’s disease.

Mitochondrial biomarkers in sporadic Parkinson’s disease

Julia Fitzgerald, Gerrit Machetanz, Anne Grünewald (LCSB, Université du Luxembourg)

Sporadic forms of Parkinson’s disease are the most common but they are difficult to model in the laboratory because there is no known gene mutation that can be introduced or corrected to generate isogenic controls. Statistically, large cohorts are needed to compare healthy individuals with sporadic Parkinson’s disease patients. This poses a problem because culturing patient-derived cell lines in parallel for such large cohorts requires specialist robotics, it is invasive for patients and is very expensive. To overcome this, we are collecting blood cells from a large cohort of Parkinson’s disease patients including sporadic and familial cases where mitochondrial proteins are affected. We will look for changes in mitochondria in these cells to try to identify subgroups of patients that may in future benefit from medicines that target mitochondrial dysfunction.