Casein kinase 1δ induces the formation of GVB-positive neurons that are resilient to tau-induced impairment of protein synthesis

The progressive intraneuronal accumulation of protein aggregates is central in the pathogenesis of several neurodegenerative diseases. Therefore, molecular pathways that mediate neuronal resilience to tau pathology present interesting targets for therapeutic intervention. To this end we investigated the mechanism and functional implications of the formation of granulovacuolar degeneration bodies (GVBs), neuron-specific lysosomal structures that form in response to pathological tau assemblies. In the present work, we show that intraneuronal tau pathology progressively induces the formation of GVB+ neurons. We demonstrate that CK1δ activity is a rate limiting step in the formation of GVB+ neurons that requires the autophagic machinery. The GVB neuronal state confers protection against tau pathology: GVB+ neurons have structural adaptations in lysosomal and ribosomal content to become resilient to tau-induced protein synthesis impairment. Moreover, GVB+ neurons are functionally resilient to tau-induced neurodegeneration and impairment of LTP-regulated protein synthesis. Altogether our results have identified CK1δ as a key regulator of a protective neuron-specific proteostatic response to tau pathology.