Investigation of the energy expenditure of human iPS cell-derived basal ganglia neurons from patients with Leigh syndrome

• Applicants: Professor Dr. Alessandro Prigione, Ph.D.; Professor Dr. Markus Schülke-Gerstenfeld
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252129655

Leigh syndrome (LS) is a severe infantile inherited neurological disorder, characterized by rapid progressive loss of motor capabilities. A pathognomonic feature of the disease is the predominant demise of neuronal cells in the basal ganglia, and specifically striatal GABAergic neurons. The genetic causes vary, comprising both nuclear genes and genes encoded by the mitochondrial DNA (mtDNA). It is believed that all mutations may share a common disruption of mitochondrial functionality and bioenergetic metabolism. However, given the lack of viable disease models, the mechanisms underlying the specific neuronal death remain to be elucidated. Furthermore, there is currently no pathogenicity-based treatment effective in ameliorating the patients`symptoms or preventing deterioration. In this project, we aim to employ the reprogramming technology to develop novel modeling tools for investigating LS. We seek to generate non-integrative induced pluripotent stem (iPS) cells from skin fibroblasts of various LS patients: harboring both nuclear mutations (in the genes PDSS2 and SURF1) and mtDNA mutations (m.9185T>C and m.8993T>G in the MT-ATP6 gene). iPS cells will be differentiated into two neuronal populations that are common in the basal ganglia, GABAergic neurons and dopaminergic neurons, employing a neural precursor cells (NPCs)-based protocol. Detailed mitochondrial and metabolic investigations will be carried out on the obtained neurons to dissect the disease-associated neuronal phenotypes. Finally, based on the identified dysfunctions, we will seek to establish image-based assays amenable to high-throughput to enable focused compound screenings on patient iPS-derived neuronal cells. If successful, this iPS cell-driven approach may shed light on the mechanisms underlying the basal ganglia involvement of LS and may pave the way to the discovery of innovative treatment strategies.

• DFG Programme: Research Grants