Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Primary Cell Line Cell, Neuron

DISEASE(S): Tauopathy

SUBMITTER: Debora Pita Illobre

LAB HEAD: Ka Wan Li

PROVIDER: PXD061887 | Pride | 2026-03-09

REPOSITORIES: Pride

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Neurons with granulovacuolar degeneration bodies are resilient to tau-induced protein synthesis impairment.

Smits Jasper F M JFM Ligthart Thijmen W TW Jorge-Oliva Marta M Middelhoff Skip S Schipper Fleur F Pita-Illobre Débora D Li Ka Wan KW Scheper Wiep W

Science advances 20260306 10

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 casein kinase 1δ (CK1δ) activity is required for GVB formation. CK1δ is sequestered in the GVB during this process in an autophagy-dependent ...[more]

PMID: 41790889

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