GVB+ neurons are resilient to tau-induced protein synthesis impairment

Summary 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 CK1δ activity is required for GVB formation. CK1δ is sequestered in the GVB during this process in an autophagy-dependent manner. 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 do not exhibit differential activation of proteostatic stress responses, but have 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. These findings provide novel opportunities for targeting neuronal resilience in tauopathies. Highlights GVB+ neurons are protected against tau-induced neurodegeneration CK1δ activity is essential for the formation of GVBs GVB+ neurons are resilient to tau-induced impairment of protein synthesis GVB+ neurons retain the capacity for LTP-regulated protein synthesis Competing Interest Statement The authors have declared no competing interest. Footnotes The manuscript was rewritten to shift the focus from the GVB to the GVB+ neuron.