The role of mitochondrial DNA mutations in neurodegenerative diseases

• Antragstellerin: Professorin Dr. Anne Grünewald
• Fachliche Zuordnung: Molekulare und zelluläre Neurologie und Neuropathologie ; Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2012 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 228485246

The aim of this project is to define the role of mitochondrial DNA (mtDNA) mutations in neurodegenerative disorders. Exemplarily, we will focus on the basal ganglia diseases Parkinsonism (PD) and Leigh¿s syndrome (LS). Despite a relatively high heritability of PD, only a minority of patients carries mutations in the PD genes known so far. Changes in the mtDNA may be an explanation for this discrepancy, since they are often disregarded or undetectable in inappropriate test tissues. For LS, mutations in mtDNA genes are a well-established cause. However, their impact on neuronal function has not yet been fully elucidated. Here, we intend to study the molecular consequences of the m.3796A>G mutation in the NADH dehydrogenase subunit 1 gene which was identified in a patient with mitochondrial co-inheritance of PD and diabetes mellitus. Furthermore, we will test the pathogenic effect of five nucleotide changes identified in different mtDNA genes of LS patients. In order to examine the role of these mutations in a biologically relevant setting, we will generate dopaminergic neurons derived from (i) human induced pluripotent stem cells and from (ii) mouse transmitochondrial embryonic stem cells. Using in vivo imaging techniques, we will study calcium homeostasis, mitochondrial function and network dynamics in single neurons of the resulting cultures. Comparison of data on multiple levels will allow identifying disease-specific phenotypes in a model-independent fashion. With this approach, we will gain fundamental insight into the pathogenic mechanisms of neurodegenerative diseases. With respect to my professional development, I will expand my methodological spectrum with key techniques of mitochondrial research during this research visit at Newcastle University. The proposed project will help me completing my habilitation thesis. Moreover, I will benefit from this experience when building a junior research group within the Section of Clinical and Molecular Neurogenetics.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: Großbritannien
• Gastgeber: Professor Dr. Douglass Turnbull