Pathogenic potential of cerebral redox imbalance and altered mitochondrial energetics in a mouse modell of Rett syndrome

• Applicant: Professor Dr. Michael Müller
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456368804

Rett syndrome (RTT), an X-chromosomal neurodevelopmental disorder, affects mostly females and arises from mutations in the transcriptional modulator MeCP2. RTT girls develop quite normal in the first 1-2 years, then cognitive impairment, irregular breathing, motor dysfunction, and epilepsy occur. A cure does not exist. The complex disease pattern includes – among others – mitochondrial impairment, redox imbalance, and oxidative tissue damage. These arise already in the brains of neonatal Rett mice and precede the typical symptoms. As working hypothesis we therefore propose that early redox alterations facilitate or provoke later symptoms and contribute to disease progression. Further, we consider intensified mitochondrial metabolism and ROS release pivotal factors of the redox-imbalance. The merits of antioxidants support these scenarios. Also, re-expressing MeCP2 in Rett mice decreased oxidant stress and ameliorated symptom severity. Yet, the exact cerebral pattern of redox-alterations and oxidant damage or the detailed mitochondrial alterations are not clear. Neither is their correlation with disease progression understood. By mapping neuronal redox conditions, we will therefore identify in male and female Rett mice the redox-impaired brain regions and match these to the oxidative tissue damage. For this, we use our optimized redox-imaging technology and unique redox-indicator Rett mice, which allow a first-time quantification of subcellular redox conditions in various brain regions and disease stages. Alterations in mitochondrial energetics will be identified by high-resolution fluorespirometry and correlated changes in mitochondrial networks and ultrastructure defined by STED- and electron-microscopy. These multiparametric data will clarify to what extent and under which conditions mitochondria contribute to the cerebral redox-imbalance, and which brain regions are struck most. The global outcome and causal interaction of mitochondrial and redox alterations will be revealed by metabolomics fingerprinting. All mice undergo behavioral phenotyping. This will allow to correlate the cerebral patterns of redox-, oxidative-, and mitochondrial alterations with disease progression, symptom severity, or even particular RTT symptoms. Also, we expect pivotal insights into the gender specific total MeCP2 deficiency (hemizygous male Rett mice) and the clinically relevant heterozygous mosaic of MeCP2 expression (female Rett mice). Finally, we will verify the mouse-model based redox- and mitochondrial alterations in Rett patient-derived cultured fibroblasts, to confirm their pathogenic relevance also for the clinical condition. All this will contribute to clarify the mechanistic role of mitochondrial alterations and associated redox changes in RTT pathogenesis, thereby revealing potential biomarkers and therapeutic targets. Information, which is highly valuable for a further development of mitochondria-directed or redox balance-based treatments.

• DFG Programme: Research Grants