Kasen, A. | bioRxiv Science

bioRxiv2025

Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency

Tau is a pathogenic protein in Alzheimers (AD) and other neurodegenerative diseases. The misfolding of tau into {beta}-sheet rich elongated filaments is thought to be a key event in disease pathogenesis, followed by subsequent templated recruitment of monomeric tau into this pathogenic form. Cryo-electron microscopy has revealed that specific tau conformations characterize different diseases. In this study, we explored how tau filament core structure and post-translational modifications in its disordered fuzzy coat influence its seeding capacity in primary neurons and mice. We show that the structure of the seeds affects seeding capacity, but that the AD tau core structure alone is insufficient to capture the full seeding capacity of AD tau. Proteolytic cleavage of AD tau which removes the fuzzy coat causes a loss in seeding capacity, as does removal of phosphorylation from the fuzzy coat by phosphatase treatment. Re-phosphorylation of phosphatase-treated AD tau by kinase treatment partially restores seeding activity. Finally, we find that filaments of recombinant tau with twelve phospho-mimetic residues (PAD12 tau) with the AD fold are able to recapitulate the seeding capacity of AD tau. Combined, these results suggest that the structure of the ordered core, together with phosphorylation in the fuzzy coat, confers the seeding capacity of tau filaments.

neuroscience↗

bioRxiv2024

Pathological α-synuclein elicits granulovacuolar degeneration independent of tau

BackgroundPathologic heterogeneity is a hallmark of Lewy body dementia (LBD), yet the impact of Lewy pathology on co-pathologies is poorly understood. Lewy pathology, containing -synuclein, is often associated with regional tau pathology burden in LBD. Similarly, granulovacuolar degeneration bodies (GVBs) have been associated with tau pathology in Alzheimers disease. Interestingly, GVBs have been detected in a broad range of neurodegenerative conditions including both -synucleinopathies and tauopathies. Despite the frequent co-occurrence, little is known about the relationship between -synuclein, tau, and granulovacuolar degeneration. MethodsWe developed a mouse model of limbic-predominant -synucleinopathy by stereotactic injection of -synuclein pre-formed fibrils (PFFs) into the basal forebrain. This model was used to investigate the relationship of -synuclein pathology with tau and GVB formation. ResultsOur model displayed widespread -synuclein pathology with a limbic predominant distribution. Aberrantly phosphorylated tau accumulated in a subset of -synuclein inclusion-bearing neurons, often colocalized with lysosomes. Many of these same neurons also contained CHMP2b- and CK1{delta}-positive granules, established markers of GVBs, which suggests a link between tau accumulation and GVB formation. Despite this observation, GVBs were also detected in tau-deficient mice following PFF-injection, suggesting that pathological -synuclein alone is sufficient to elicit GVB formation. ConclusionsOur findings support that -synuclein pathology can independently elicit granulovacuolar degeneration. The frequent co-accumulation of tau and GVBs suggests a parallel mechanism of cellular dysfunction. The ability of -synuclein pathology to drive GVB formation in the absence of tau highlights the broader relevance of this process to neurodegeneration with relevance to the pathobiology of LBD.

neuroscience↗