The central nervous system component of peripheral neuropathies: a crucial liaison between microglia and motor neurons?

• Applicant: Dr. Mar Bosch Queralt
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Developmental Neurobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501294335

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy, characterized by progressive impairment of motor and sensory functions. While the underlying pathological hallmarks of a primary glial defect and secondary axonal degeneration in peripheral nerves have been extensively studied in the last decades, pathomechanistic processes in the central nervous system (CNS) remain largely unexplored in CMT1A disease. Here, we hypothesize that peripheral motor axon impairment due to a primary Schwann cell dysfunction has a detrimental impact on motor neuron (MN) integrity in the spinal cord that significantly contributes to disease manifestation and progression. Specifically, we propose that (mal)adaptive signaling from MN cell bodies induces microglia-mediated inflammatory processes and abnormal MN synaptic connectivity. Indeed, our preliminary studies in a CMT1A mouse model suggest molecular changes in the phenotype of ventral grey matter microglia. Notably, these changes emerged already at postnatal disease stages, before degeneration of MN cell bodies, which represents a later stage feature of CMT1A disease. A characterization of potential microglia-MN interaction sites in CMT1A rodent models revealed close contacts of microglia ramifications with cholinergic presynaptic inputs (C-boutons) to MN somata, proximal to postsynaptic ‘clusters’ of the growth factor Neuregulin-1 (NRG1). Importantly, NRG1 cluster size in MNs was increased at postnatal stages, indicating differential production, processing or transport of NRG1 in CMT1A. Together, these preliminary data suggest a specific, early onset response of spinal cord ventral horn microglia, which we hypothesize to derive from altered local signalling cues of diseased MN in CMT1A disease. Using a combination of cutting-edge single-cell transcriptomics, high-end imaging strategies, including tissue clearing and super-resolution microscopy, as well as several mouse models of peripheral nerve disease, we here aim at elucidating the reciprocal microglia-to-MN communication in CMT1A throughout disease course, with the ultimate goal to identify new therapeutic approaches for the currently untreatable inherited peripheral neuropathies.

• DFG Programme: WBP Position