Molecular Disease Stages of Oligodendrocytic and Neuronal Tau Burden in Progressive Supranuclear Palsy

This bioRxiv preprint investigates how cell type-specific molecular programs evolve with tau pathology in progressive supranuclear palsy (PSP), a primary tauopathy characterized by 4R tau accumulation in neurons, oligodendrocytes, and astrocytes. The authors performed single-nucleus ATAC-seq and RNA-seq on postmortem frontal cortex from 8 PSP patients and 8 matched controls, profiling over 144,000 nuclei. Tau pathology burdens (neurofibrillary tangles, coiled bodies, tufted astrocytes) were quantified on AT8-immunostained sections from the same individuals. Integrated analyses—including differential expression, transcription factor motif enrichment, weighted gene co-expression network analysis, and pseudotime modeling anchored to cell type-specific tau burden—delineated molecular pseudo-progression trajectories.

Key findings: PSP brains showed selective depletion of excitatory deep-layer neurons and oligodendrocyte subclusters, with relative preservation of inhibitory neurons and vascular cells. Genetic risk enrichment localized to astrocytes and oligodendrocytes, while excitatory neurons exhibited the greatest transcriptional dysregulation. Oligodendrocyte pseudo-progression transitioned from homeostatic myelination (MBP, MOBP) through glucocorticoid-responsive stress (FKBP5, ZBTB16) to compensatory myelination (PLP1, CNP) and proteostasis stress (UCHL1, CYRAB, CLU). Neuronal pseudo-progression revealed early dysregulation of synaptic (RORB2, NRG3, NPTX1), microtubule dynamics (KIF2C, RAB27B, TUBA/B), and survival (MEG3, FTX) pathways, with a transient increase in neuron-glia interactions (GRIP, CNTNAP4, ERBB4), converging late on ribosomal translation and vesicular trafficking modules across all neuronal subtypes. Cross-modal integration with CSF proteomics identified concordant glial reactivity, axonal injury, and synaptic markers in inhibitory neurons, oligodendrocytes, and excitatory deep-layer neurons.

These results suggest PSP pathogenesis combines glial genetic susceptibility with staged, cell type-specific transcriptional dysfunction, providing a molecular framework linking glial biology to neurodegeneration in primary tauopathy.