Project Details
Projekt
Epigenetic control of neurogenesis and neuronal loss in neuroinflammation
Applicants
Dr. Jan Broder Engler; Dr. Sina Cathérine Rosenkranz
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 523862973
Cognitive impairment, fatigue and depression are highly prevalent in people with multiple sclerosis (MS) and profoundly impact their quality of life. The cause of these symptoms is likely related to neuronal loss in the hippocampus which is not currently tackled by available therapies. Moreover, the underlying cellular and molecular mechanisms, including the relative contribution of disrupted adult neurogenesis and inflammatory neurodegeneration remain unclear. By neuronal translatome profiling during inflammation in the spinal cord, we recently identified a prominent role of the epigenetic regulator and histone methyl transferase G9a in promoting neurodegeneration, which might also be involved in hippocampal pathology. In the inflamed hippocampus, we detected a significant IBA1 microglia activation, a reduction of synaptic contacts and a reduction of mature NeuN-positive cells as well as doublecortin (DCX)-positive immature neurons. This indicated an impairment of neurogenesis by hippocampal inflammation. We also found the levels of H3K9me2, the main down-stream target of G9a, to be induced in NeuN-positive neuronal nuclei in the inflamed hippocampus, while G9a inhibition led to a complete rescue to healthy baseline levels. Moreover, G9a inhibition increased the number of DCX-positive immature neurons in the inflamed dentate gyrus suggesting a role for G9a in limiting neurogenesis. Together, we hypothesize that neuroinflammation leads to epigenetic and transcriptional dysregulation in neuronal progenitor cells which results in impaired neurogenesis, reduced synaptic plasticity and neuronal degeneration. In this proposal we aim to disentangle the epigenetic control of neurogenesis and neuronal loss in neuroinflammation in order to derive novel treatment targets to counteract hippocampal pathology in MS.
DFG Programme
Research Units
