| Mechanism summary | Upstream trigger / risk | Key evidence / quantitative result | Primary cell types (CL suggestion) | Affected anatomical regions (UBERON suggestion) | GO biological process term suggestions | Evidence source DOI / year |
|---|---|---|---|---|---|---|
| 4R tau accumulation and aggregation in neurons and glia drives PSP neurodegeneration through hyperphosphorylated tau inclusions, impaired proteostasis, and cell-to-cell seeding | Sporadic PSP biology; MAPT-linked 4R tau predisposition; tau seeding/propagation | PSP is neuropathologically defined by aggregated 4R tau in neurons, astrocytes, and oligodendrocytes; tau inclusions include neurofibrillary tangles, tufted astrocytes, and coiled bodies; MAPT expression is preserved in all 3 cell types with tau aggregates, supporting ongoing local tau production that can feed aggregation/seeding (pqac-00000017, pqac-00000024, pqac-00000038) | neuron (CL:0000540); astrocyte (CL:0000127); oligodendrocyte (CL:0000128) | subthalamic nucleus (UBERON:0001906); globus pallidus (UBERON:0002427); midbrain (UBERON:0001891); cerebellum (UBERON:0002037) | protein phosphorylation (GO:0006468); protein aggregation (GO:0070207); microtubule cytoskeleton organization (GO:0000226); neuron death (GO:0070997) | 10.1002/mds.26987 (2017); 10.1007/s00401-024-02823-w (2024); 10.1007/s00401-023-02604-x (2023) |
| MAPT haplotype-associated increase in 4R tau mRNA likely acts upstream of tau aggregation | 17q21.31 inversion / MAPT H1 haplotype; structural variation around MAPT/KANSL1 | H1 haplotype is the strongest common genetic risk with OR ~5.6; bulk RNA-seq showed increased total tau and 4R tau transcripts in PSP cerebellum and increased 4R tau reads in temporal cortex; 4R tau mRNA levels were significantly associated with H1 in temporal cortex, supporting an upstream splicing/expression mechanism (pqac-00000020, pqac-00000022) | excitatory/inhibitory neuron (CL:0000540); astrocyte (CL:0000127); oligodendrocyte (CL:0000128) | cerebellum (UBERON:0002037); temporal cortex (UBERON:0016529); midbrain (UBERON:0001891) | regulation of mRNA splicing, via spliceosome (GO:0048024); RNA processing (GO:0006396); regulation of gene expression (GO:0010468) | 10.1186/s13024-024-00747-3 (2024); 10.1186/s40478-024-01839-3 (2024) |
| Integrated stress response / EIF2 signaling and PERK(EIF2AK3) activation links tau burden to maladaptive stress signaling and downstream apoptosis/autophagy failure | Genetic risk at EIF2AK3; chronic proteotoxic and ER stress induced by tau pathology | Single-nucleus RNA-seq of 50,708 nuclei from PSP diencephalon identified EIF2 signaling activated across vulnerable cell types; activated eIF2α positively correlated with tau pathology burden in subthalamic nucleus and thalamus and colocalized with p-tau-positive neurons and ALDH1L1-positive astrocytes; GWAS had already implicated EIF2AK3/PERK as a PSP risk locus (pqac-00000023, pqac-00000024) | neuron (CL:0000540); astrocyte (CL:0000127); oligodendrocyte (CL:0000128); microglial cell (CL:0000129) | subthalamic nucleus (UBERON:0001906); thalamus (UBERON:0001897); globus pallidus (UBERON:0002427); visual cortex / occipital cortex as relatively spared comparator (UBERON:0001870) | integrated stress response signaling (GO:0034976-related); response to endoplasmic reticulum stress (GO:0034976); translational initiation (GO:0006413); regulation of apoptotic process (GO:0042981); autophagy (GO:0006914) | 10.1007/s00401-024-02823-w (2024) |
| Axon-guidance, synaptic, vesicle-cytoskeletal, and cytokine-signaling modules are dysregulated in PSP CSF, consistent with circuit dysfunction downstream of tauopathy | Tau-mediated network degeneration and synaptic/axonal injury | SOMAmer CSF proteomics found 155/5,026, 959/7,595, and 321/5,026 differentially expressed SOMAmers across original, validation, and neuropathology-confirmed cohorts; three coexpression modules implicated synaptic function/JAK-STAT (beta = -0.044, corrected p = 0.002), vesicle-cytoskeletal trafficking (beta = 0.039, p = 0.007), and cytokine-cytokine receptor interaction (beta = -0.032, p = 0.035); axon guidance was the top dysregulated pathway across cohorts and an axon-guidance panel gave AUC 0.924/0.815/0.932 (pqac-00000009, pqac-00000032) | neuron (CL:0000540); synapse-associated neuronal populations; astrocyte (CL:0000127) | dorsal midbrain (UBERON:0001891); globus pallidus (UBERON:0002427); subthalamic nucleus (UBERON:0001906) | axon guidance (GO:0007411); synapse organization (GO:0050808); vesicle-mediated transport (GO:0016192); JAK-STAT cascade (GO:0007259); cytokine-mediated signaling pathway (GO:0019221) | 10.1212/WNL.0000000000209585 (2024) |
| Complement/C4A-associated oligodendrocyte activation suggests glial and myelin-related mechanisms in PSP | PSP GWAS risk architecture; oligodendrocyte-specific regulatory effects; complement dysregulation | Integrative genetics/transcriptomics/histology work implicated glial activation, oligodendrocyte-specific epigenomic/eQTL effects at many loci, elevated C4A expression, and histologic colocalization of tau aggregates with C4 complement in oligodendrocytes; this supports complement-associated oligodendroglial pathology as part of etiopathogenesis (pqac-00000005) | oligodendrocyte (CL:0000128); astrocyte (CL:0000127); microglial cell (CL:0000129) | white matter (UBERON:0002316); globus pallidus (UBERON:0002427); brainstem (UBERON:0002298) | complement activation (GO:0006956); gliogenesis (GO:0042063); myelination (GO:0042552); regulation of immune response (GO:0050776) | 10.1101/2023.11.09.565552 (2024 preprint) |
| White-matter DNA methylation changes implicate Wnt signaling, ER stress, mitochondrial dysfunction, RNA interference, and endosomal transport as convergent downstream molecular programs | Epigenetic dysregulation in parkinsonian white matter; shared but PSP-relevant white-matter pathology | EPIC-array profiling of frontal lobe white matter from PSP (n = 16) and controls identified co-methylation signatures affecting Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport; PSP white matter showed disease-specific and shared alterations relevant to neurodegeneration (pqac-00000021) | oligodendrocyte (CL:0000128); astrocyte (CL:0000127); microglial cell (CL:0000129) | frontal lobe white matter (UBERON suggestion: frontal lobe UBERON:0001870 + white matter UBERON:0002316); cerebrum white matter (UBERON:0002316) | Wnt signaling pathway (GO:0016055); response to endoplasmic reticulum stress (GO:0034976); mitochondrial ATP synthesis coupled electron transport (GO:0042775); endosomal transport (GO:0016197); RNA interference (GO:0016246) | 10.1007/s00401-024-02764-4 (2024) |
| Neuroinflammatory markers galectin-10 and CTLA-4 track clinical severity, indicating immune activation as a disease-modifying downstream process | Tau-triggered glial/immune activation; inflammatory remodeling of CSF proteome | In CSF proteomics, galectin-10 and CTLA-4 correlated with PSP Rating Scale scores across cohorts; inflammatory and cytokine-cytokine receptor interaction modules were also identified, supporting ongoing neuroimmune involvement in disease progression (pqac-00000009, pqac-00000032) | microglial cell (CL:0000129); astrocyte (CL:0000127); infiltrating immune cell / T cell (CL:0000084 suggestion) | CSF-reflective pathology from subthalamic nucleus (UBERON:0001906), globus pallidus (UBERON:0002427), and dorsal midbrain (UBERON:0001891) | inflammatory response (GO:0006954); cytokine-mediated signaling pathway (GO:0019221); regulation of immune system process (GO:0002682) | 10.1212/WNL.0000000000209585 (2024) |


*Table: This table summarizes major molecular and cellular mechanisms implicated in progressive supranuclear palsy, linking genetic risk, tau biology, stress signaling, white-matter epigenetics, and neuroinflammation to vulnerable cell types and brain regions. It is useful for knowledge-base annotation because it also suggests ontology terms for cells, anatomy, and biological processes.*