High-throughput microscopy exposes a pharmacological window in which dual leucine zipper kinase inhibition preserves neuronal network connectivity

Marlies Verschuuren, Peter Verstraelen, Gerardo Garcia-Diaz Barriga, Ines Cilissen, Emma Coninx, Mieke Verslegers, Peter Larsen, Rony Nuydens, Winnok H. De Vos

    Research outputpeer-review


    Therapeutic developments for neurodegenerative disorders are redirecting their focus to the mechanisms that contribute to neuronal connectivity and the loss thereof. Using a high-throughput microscopy pipeline that integrates morphological and functional measurements, we found that inhibition of dual leucine zipper kinase (DLK) increased neuronal connectivity in primary cortical cultures. This neuroprotective effect was not only observed in basal conditions but also in cultures depleted from antioxidants and in cultures in which microtubule stability was genetically perturbed. Based on the morphofunctional connectivity signature, we further showed that the effects were limited to a specific dose and time range. Thus, our results illustrate that profiling microscopy images with deep coverage enables sensitive interrogation of neuronal connectivity and allows exposing a pharmacological window for targeted treatments. In doing so, we revealed a broad-spectrum neuroprotective effect of DLK inhibition, which may have relevance to pathological conditions that ar.e associated with compromised neuronal connectivity.
    Original languageEnglish
    Pages (from-to)1-16
    Number of pages16
    JournalActa Neuropathologica Communications
    Issue number93
    StatePublished - 4 Jun 2019

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