Oligodendrocyte-microglia communication in the initiation of chronic secondary neuroinflammation

• Applicant: Dr. Janos Groh
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398078851

Genetically caused neurological disorders of the CNS usually lead to chronic disability, substantial decline in quality of life and are often not or poorly treatable. Many of them are accompanied by neuroinflammation of uncertain pathogenic relevance. Using a strategy allowing controlled insertion of two (proteolipid protein) PLP1 gene mutations previously described in human multiple sclerosis (MS) patients, we have generated mouse models reflecting several important aspects of chronic progressive multiple sclerosis (PMS) but also hereditary spastic paraplegia (HSP) including myelin abnormalities, axonal perturbation, neuron loss and moderate neuroinflammation. In favour of the hypothesis that primary oligodendroglial perturbation can trigger pathologically-relevant secondary neuroinflammation that drives neurodegeneration, genetic inactivation experiments unequivocally demonstrated a substantial disease-modifying impact of low-grade inflammation by adaptive immune cells in these models. The present proposal is aimed to identify molecular signals and cellular interactions of mutant oligodendrocytes and sialoadhesin-positive (Sn+) activated microglia that initiate and promote this detrimental secondary immune reaction in these newly generated mice in comparison with models for a PLP1-related leukodystrophy and a genetically unrelated neurodegenerative lysosomal storage disease also associated with early axonal damage and neuroinflammation. Identifying common and distinct inflammation-related disease pathways in these models will provide us with pathomechanistic insights as well as putative therapeutic targets for treatment of PMS and some genetically-mediated disorders of the nervous system accompanied by pathogenic neuroinflammation.

• DFG Programme: Research Grants