The triple pathology of Parkinson’s disease: α-Synuclein, Tau, and Inflammasome

Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder classically defined by nigrostriatal dopaminergic degeneration and the accumulation of α-synuclein–containing Lewy bodies. Increasing evidence, however, indicates that PD is a heterogeneous, multisystem disease that involves widespread pathology beyond the central nervous system and cannot be explained by a single pathogenic mechanism. In addition to α-synuclein aggregation, neuroinflammation and tau pathology have emerged as key contributors to disease initiation and progression. In particular, activation of the innate immune system through the NLRP3 inflammasome has been implicated in both central and peripheral PD-related inflammation. Moreover, recent data suggest that tau pathology may occur early in parkinsonian disorders and interact synergistically with α-synuclein. We investigated the hypothesis that PD is characterized by a “triple pathology,” involving α-synuclein aggregation, tau dysregulation, and inflammasome activation, with a specific focus on the gut–brain axis and prodromal stages of the disease. Materials and Methods The experimental work comprised complementary human and animal studies. In the human study, colon biopsies were obtained from patients with early-stage PD, individuals with isolated REM sleep behavior disorder (iRBD) as a prodromal synucleinopathy, and age- and sex-matched healthy controls. All participants underwent standardized neurological and gastroenterological evaluations. Colonic tissue samples were analyzed using Western blotting and immunofluorescence to assess α-synuclein deposition, NLRP3 inflammasome components (NLRP3, ASC, caspase-1, and IL-1β), immune cell markers, and proteins related to epithelial and vascular barrier integrity. Quantitative image analysis was performed using confocal microscopy. To investigate tau pathology and its interaction with α-synuclein, an A53T α-synuclein transgenic mouse model was employed, alongside analyses of human tissue samples. Tau phosphorylation, aggregation, and synaptic markers were assessed using biochemical and histological approaches. Together, these methods allowed an integrated evaluation of protein aggregation, innate immune activation, and peripheral tissue involvement in PD. Results Colonic biopsies from both PD and iRBD subjects showed significantly increased α-synuclein accumulation compared with controls. This was accompanied by clear evidence of NLRP3 inflammasome activation, including increased expression of inflammasome components and the presence of ASC specks, particularly within intestinal macrophages. Importantly, inflammasome activation was already detectable in iRBD subjects, indicating that peripheral innate immune dysregulation occurs early, before the onset of overt motor symptoms. In parallel, markers of intestinal epithelial tight junctions and endothelial permeability were altered, suggesting compromised gut barrier integrity in both prodromal and early PD. In the experimental models, pathological α-synuclein was associated with increased tau phosphorylation and aggregation. Tau alterations were linked to synaptic dysfunction and neuronal vulnerability and appeared to be exacerbated by α-synuclein pathology. Conversely, tau pathology facilitated α-synuclein aggregation, supporting a bidirectional and synergistic interaction between the two proteins. These findings indicate that tau is not merely a late or secondary feature of PD but may represent an early and active contributor to neurodegeneration. Conclusions The results suggest that Parkinson’s disease is characterized by a triple pathology involving α-synuclein aggregation, tau dysregulation, and NLRP3 inflammasome–mediated inflammation. Peripheral tissues, particularly the gut, exhibit early pathological changes, including protein aggregation, immune activation, and barrier dysfunction, supporting a key role for the gut–brain axis in PD pathogenesis. The presence of inflammasome activation and tau pathology in prodromal stages suggests that these processes precede and potentially drive central neurodegeneration. Collectively, these findings support a multi-hit, systemic model of PD and highlight inflammation and mixed proteinopathy as promising targets for early biomarkers and disease-modifying therapeutic strategies.