Tau isoform imbalance and aggregation are pathological hallmarks of X-linked dystonia-parkinsonism
Tauopathies encompass diverse neurodegenerative diseases unified by aberrant patterns of tau deposition in brain. Although most appear sporadic, some are linked to genetic etiologies that offer unique mechanistic insights. Here we report that X-linked Dystonia-Parkinsonism (XDP), caused by a non-coding retrotransposon-associated repeat insertion in TAF1, involves a significant imbalance of tau isoforms and the accumulation of hyperphosphorylated, four-repeat tau in the brain. In striatal tissue, both misfolded tau accumulation, predominantly in astrocytes, and MAPT exon 10 inclusion correlated with repeat length within the causal insertion. Transcriptomic profiling across brain regions revealed dysregulation of known tau-related pathways. Levels of phosphorylated tau181, glial fibrillary acidic protein, and neurofilament light chain were elevated in patient plasma and discriminated XDP from controls. These findings implicate defective tau proteostasis as a key pathogenic mechanism and position XDP as a genetic model for uncovering cellular drivers that may disrupt tau in other more common neurodegenerative diseases.