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

Abstract

In Alzheimers 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 CK1{delta} activity is required for GVB formation. CK1{delta} 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 CK1{delta} 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. HighlightsO_LIGVB+ neurons are protected against tau-induced neurodegeneration C_LIO_LICK1{delta} activity is essential for the formation of GVBs C_LIO_LIGVB+ neurons are resilient to tau-induced impairment of protein synthesis C_LIO_LIGVB+ neurons retain the capacity for LTP-regulated protein synthesis C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/645932v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@cda628org.highwire.dtl.DTLVardef@157bcb8org.highwire.dtl.DTLVardef@126dbe6org.highwire.dtl.DTLVardef@2efe8f_HPS_FORMAT_FIGEXP M_FIG C_FIG