Journal Article

Pathological α-synuclein elicits granulovacuolar degeneration independent of tau

Williams, Erin T., Dues, Dylan J., Moore, Darren J., Kasen, Alysa, Erb, Madalynn L., Henderson, Michael X., Nguyen, An Phu Tran, Vatsa, Naman

2025

Overview

Background Pathologic heterogeneity is a hallmark of Lewy body dementia (LBD), yet the impact of Lewy pathology on co-pathologies is poorly understood. Lewy pathology, containing α-synuclein, is often associated with regional tau pathology burden in LBD. Similarly, granulovacuolar degeneration bodies (GVBs) have been associated with tau pathology in Alzheimer’s disease. Interestingly, GVBs have been detected in a broad range of neurodegenerative conditions including both α-synucleinopathies and tauopathies. Despite the frequent co-occurrence, little is known about the relationship between α-synuclein, tau, and granulovacuolar degeneration. Methods We developed a mouse model of limbic-predominant α-synucleinopathy by stereotactic injection of mouse α-synuclein pre-formed fibrils (PFFs) into the basal forebrain. This model was used to investigate the relationship of α-synuclein pathology with tau and GVB formation. Results Our model displayed widespread α-synuclein pathology with a limbic-predominant distribution. Aberrantly phosphorylated tau accumulated in a subset of α-synuclein inclusion-bearing neurons, often colocalized with lysosomes. Many of these same neurons also contained CHMP2b- and CK1δ-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 α-synuclein alone is sufficient to elicit GVB formation. Conclusions Our findings support that α-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 α-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.

• Publisher: BioMed Central,BMC
• Subject: Alpha-synuclein / alpha-Synuclein - metabolism / alpha-Synuclein - toxicity / Animals / Biomedical and Life Sciences / Biomedicine / Disease Models, Animal / Granulovacuolar degeneration / Humans / Inclusion Bodies - metabolism / Inclusion Bodies - pathology / Lewy Body Disease - metabolism / Lewy Body Disease - pathology / Lewy pathology / Mice / Mice, Transgenic / Neurodegeneration / Neurology / Neurons - metabolism / Neurons - pathology / Neurosciences / Protein aggregation / Tau / tau Proteins - metabolism