MAPT genotype-dependent mitochondrial aberration and ROS production trigger dysfunction and death in cortical neurons of patients with hereditary FTLD
Lisanne Korn,
Anna M. Speicher,
Christina B. Schroeter,
Lukas Gola,
Thilo Kaehne,
Alexander Engler,
Paul Disse,
Juncal Fernández-Orth,
Júlia Csatári,
Michael Naumann,
Guiscard Seebohm,
Sven G. Meuth,
Hans R. Schöler,
Heinz Wiendl,
Stjepana Kovac,
Matthias Pawlowski
Affiliations
Lisanne Korn
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Anna M. Speicher
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Christina B. Schroeter
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Lukas Gola
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Thilo Kaehne
Institute of Experimental Internal Medicine, Otto-von-Guericke University, Magdeburg, Germany
Alexander Engler
Institute of Experimental Internal Medicine, Otto-von-Guericke University, Magdeburg, Germany
Paul Disse
Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany; Chemical Biology of Ion Channels (Chembion), GRK 2515, University of Münster, 48149, Münster, Germany
Juncal Fernández-Orth
Department of Pediatric Hematology and Oncology, University Medical Center Freiburg, Germany
Júlia Csatári
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Michael Naumann
Institute of Experimental Internal Medicine, Otto-von-Guericke University, Magdeburg, Germany
Guiscard Seebohm
Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany; Chemical Biology of Ion Channels (Chembion), GRK 2515, University of Münster, 48149, Münster, Germany
Sven G. Meuth
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Hans R. Schöler
Department of Cell and Developmental Biology, Max-Planck-Institute for Molecular Biomedicine, Münster, Germany; Medical Faculty, University of Münster, Münster, Germany
Heinz Wiendl
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Stjepana Kovac
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany
Matthias Pawlowski
Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany; Corresponding author. Department of Neurology with Institute of Translational Neurology University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.
Tauopathies are a major type of proteinopathies underlying neurodegenerative diseases. Mutations in the tau-encoding MAPT-gene lead to hereditary cases of frontotemporal lobar degeneration (FTLD)-tau, which span a wide phenotypic and pathological spectrum. Some of these mutations, such as the N279K mutation, result in a shift of the physiological 3R/4R ratio towards the more aggregation prone 4R isoform. Other mutations such as V337M cause a decrease in the in vitro affinity of tau to microtubules and a reduced ability to promote microtubule assembly. Whether both mutations address similar downstream signalling cascades remains unclear but is important for potential rescue strategies. Here, we developed a novel and optimised forward programming protocol for the rapid and highly efficient production of pure cultures of glutamatergic cortical neurons from hiPSCs. We apply this protocol to delineate mechanisms of neurodegeneration in an FTLD-tau hiPSC-model consisting of MAPTN279K- or MAPTV337M-mutants and wild-type or isogenic controls. The resulting cortical neurons express MAPT-genotype-dependent dominant proteome clusters regulating apoptosis, ROS homeostasis and mitochondrial function. Related pathways are significantly upregulated in MAPTN279K neurons but not in MAPTV337M neurons or controls. Live cell imaging demonstrates that both MAPT mutations affect excitability of membranes as reflected in spontaneous and stimulus evoked calcium signals when compared to controls, albeit more pronounced in MAPTN279K neurons. These spontaneous calcium oscillations in MAPTN279K neurons triggered mitochondrial hyperpolarisation and fission leading to mitochondrial ROS production, but also ROS production through NOX2 acting together to induce cell death. Importantly, we found that these mechanisms are MAPT mutation-specific and were observed in MAPTN279K neurons, but not in MAPTV337M neurons, supporting a pathological role of the 4R tau isoform in redox disbalance and highlighting MAPT-mutation specific clinicopathological-genetic correlations, which may inform rescue strategies in different MAPT mutations.
