Lewy bodies are surrounded by granulovacuolar degeneration bodies in dementia with Lewy bodies.

Abstract

Lewy bodies (LBs), composed primarily of aggregated α-synuclein (α-syn), are the pathological hallmark of Lewy body diseases, including Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies (DLB). Despite their diagnostic significance, the mechanisms underlying LB formation and their contribution to neurodegeneration remain poorly understood. Previous studies have reported that structures labelled with ubiquitin phosphorylated at serine 65 (p-Ub^S65)-a marker of mitophagy-localise both at the periphery of and within LBs. This study aimed to further characterise these structures and clarify their relationship to α-syn pathology in DLB. Immunofluorescence analysis of post-mortem DLB brain tissue revealed intermittent co-localisation of p-Ub^S65+ puncta with conventional mitochondrial markers. Given previous findings that granulovacuolar degeneration bodies (GVBs)-vesicular structures frequently associated with tau pathology, itself a concomitant feature of DLB-are immunopositive for p-Ub^S65, we next examined whether peri-LB p-Ub^S65+ structures are actually GVBs. p-Ub^S65 puncta co-stained with established GVB markers including charged multivesicular body protein 2B (CHMP2B) and casein kinase 1 delta (CK1D), and, more variably with hyperphosphorylated tau (AT8), across multiple brain regions associated with LB pathology. Notably, GVB abundance within the anterior cingulate gyrus was found to positively correlate with p-α-syn^S129 burden. In summary, p-Ub^S65+ GVBs, containing both auto- and endolysosomal material, cluster around LBs in DLB. Frequently immunoreactive for tau, these hybrid waste vesicles provide a tangible mechanistic link between α-syn and tau pathology and may offer new insight into the processes underlying LB formation in DLB.