The miR-92a–Cpeb3 network in inflammation-induced neurodegeneration

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Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system (CNS), which is characterized by a wide spectrum of neurological symptoms. These are primarily caused by inflammation-driven neuroaxonal and synaptic injury, irrespective of prevailing MS subtype. Since progression of MS is not sufficiently mitigated by the existing immunomodulatory drugs, neuroprotective interventions are an urgent unmet need. Therefore, revealing neuron-intrinsic mechanisms of protection against inflammation-induced neurodegeneration, holds the promise to tailor neuroprotective drugs that can eventually halt neurological progression. Recently, we demonstrated that inflammatory stress results in a broad neuron-specific transcriptional and translational response. A mechanism that quickly rebalances such inflammatory perturbations in a cell-specific manner is post-transcriptional regulation of mRNA transcripts by microRNAs (miRNAs). However, knowledge about the functional role of neuronal miRNAs and its dependent regulatory pathways is sparse, but could reveal such neuroprotective drug targets. For these reasons, in our previously funded project, we profiled neuron-specific miRNA–mRNA networks in CNS inflammation, which led to the discovery of the miR-92a–Cpeb3 network. Functional analyses revealed that miR-92a is induced in neurons during EAE and transcriptionally upregulated by glutamate stress. Moreover, it strongly protected from glutamate-induced neuronal cell death. By elaborate bioinformatic analyses and subsequent validation, we identified the RNA-binding protein Cpeb3 as a prominent target transcript of miR-92a that was downregulated in neurons during EAE and upon neuronal glutamate stress. Consistent with miR-92a overexpression, Cpeb3 deletion in primary neurons revealed improved survival upon glutamate application. Using gene-deleted mice we also observed the reciprocal effects of miR-92a and Cpeb3 on the clinical outcome of EAE mice. However, many different aspects of how the newly discovered miR-92a–Cpeb3 network modulates neurodegeneration remains enigmatic. Thus, in this renewal application, we propose to identify the cellular regulation and spatial specificity of this network as well as to profile the downstream components. These will then be mechanistically dissected for their neuroprotective properties. We will further explore and validate our findings in preclinical studies as well as in human cells and tissues. Besides the opportunity to intervene in inflammation-induced neurodegeneration by translating our mechanistic findings into neuroprotective drug targets, this research offers far-reaching insights into basic principles of neuronal miRNA–mRNA networks and their contribution to neuronal signaling and survival.