Casein kinase 1δ-regulated formation of GVBs induces resilience to tau pathology-mediated protein synthesis impairment

In Alzheimer’s disease, many surviving neurons with tau pathology contain granulovacuolar degeneration bodies (GVBs), neuron-specific lysosomal structures induced by pathological tau assemblies. This could indicate a neuroprotective role for GVBs, however, the mechanism of GVB formation and its functional implications are elusive. Here, we demonstrate that GVB formation depends on CK1δ activity and basal autophagy. We show that neurons with GVBs (GVB+) are resilient to tau-induced impairment of global protein synthesis and are protected against tau-mediated neurodegeneration. GVB+ neurons have multiple adaptations to counteract the tau pathology-induced decline in protein synthesis, including increased ribosomal content. Importantly, unlike neurons without GVBs, GVB+ neurons fully retain the capacity to induce long-term potentiation-induced protein synthesis in the presence of tau pathology. Our results have identified CK1δ as a key regulator of GVB formation that confers a protective neuron-specific proteostatic stress response to tau pathology. Our findings provide novel opportunities for targeting neuronal resilience in tauopathies.