Human Wild-Type α-Synuclein Drives Progressive Tau Pathology in a Disease-Relevant Mouse Model of Synucleinopathy

Tau pathology, characterized by the aberrant aggregation and accumulation of tau in neurons and glial cells, plays a critical role in the onset and progression of multiple neurodegenerative diseases. Although synucleinopathies such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are primarily defined by intracytoplasmic inclusions of α-Synuclein (α-Syn), they frequently exhibit substantial tau co-pathology. Emerging genetic and pathological evidence suggests a mechanistic interplay between α-Syn and tau that amplifies their aggregation and accelerates neurodegeneration. In this study, we systematically investigated the temporal progression of tau pathology in a transgenic PD mouse model that overexpresses human wild-type (WT) α-Syn (hSyn mice). Prior work has shown that this model develops α-Syn pathology across key brain regions, including the substantia nigra, cortex, hippocampus, and striatum, accompanied by microglial activation and synaptic dysfunction. Using a combination of biochemical, biophysical, and immunological approaches, we demonstrate a progressive accumulation of hyperphosphorylated tau, as well as soluble and insoluble tau aggregates, in the brains of hSyn mice. Electron microscopy of insoluble fractions reveals abundant fibrillar structures, while mass spectrometry confirms that these fibrils consist of both α-Syn and tau. Notably, these pathologies are absent in WT littermates, suggesting that tau aggregation arises as a consequence of α-Syn overexpression rather than normal aging. Collectively, our findings establish a mechanistic link between α-Syn and tau aggregation, identifying tau as an active contributor to α-Syn–driven neurodegeneration. This study provides direct experimental evidence that tau co-pathology contributes to disease progression in synucleinopathies, underscoring the therapeutic potential of targeting pathological tau to mitigate neurodegeneration in PD, DLB, and related disorders.