Sphingosine-1-phosphate-receptor modulation

The primary focus of our current research is on oligodendrocyte pathologies, the sphingosine-1-phosphate receptor (S1PR) system, and how this system is modulated by established pharmaceuticals, particularly Siponimod. We hypothesize that in diseases like multiple sclerosis, central cytoprotective effects of S1PR modulators, such as Siponimod, are mainly mediated through agonistic interactions with the S1PR5 receptor subtype. Oligodendrocytes, which express this receptor subtype at high levels, may be protected from cellular stress, degeneration, and demyelination as a result. Our central animal model for this research is the cuprizone model, which allows us to study pronounced oligodendrogliopathy, subsequent demyelination, glial cell activation, and immune cell recruitment in a non-autoimmune context. We use clinically established drugs (e.g., Siponimod) and various (conditional) mouse mutants in our investigations. The research is conducted on both murine and human brain tissue, employing established laboratory techniques such as paraffin and cryosectioning, immunohistochemistry, fluorescence microscopy, electron microscopy, real-time PCR and lipidomics.

Regional oligodendrocyte vulnerability

Demyelination, characterized by oligodendrocyte loss and myelin damage, is a hallmark of neurological diseases like multiple sclerosis (MS). The cuprizone mouse model induces region-specific demyelination, affecting areas such as the corpus callosum and cortex, while regions like the commissura anterior, fimbria hippocampi and spinal cord remain largely unaffected ('pseudoresistant'). This study investigates regional differences in oligodendrocyte vulnerability, the role of cellular stress responses and the potential modulatory contribution of microglial CD83 expression.

Loss of Oligodendrocyte Transcription Factors under Metabolic Stress

Oligodendrocyte transcription factor 2 (OLIG2) is a sequence-specific DNA-binding protein that plays a crucial role in oligodendrocyte lineage progression and early differentiation. While commonly used as a pan-oligodendrocyte marker, its stability and functional relevance under pathological conditions remain poorly understood. Recent in vitro studies indicate that oligodendrocyte lineage-enriched transcripts are particularly vulnerable to suppression during integrated stress responses, which may contribute to oligodendrocyte dysfunction and subsequent myelin degeneration. We hypothesize that OLIG2 protein expression in oligodendrocytes is dynamically regulated in response to cellular stress and that its loss may reflect an adaptive or maladaptive response. Here we test whether OLIG2 expression in oligodendrocytes is stable or altered during metabolic stress in vivo.