Tau-Fyn signaling at postsynaptic sites is implicated

The gap

Evidence profile

Stated in the future work and inline gaps and cells future research and abstract sections of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 4 representative gaps

• Tau conformation, distribution and PET imaging correlations in progressive supranuclear palsy (2026) · Translational Neurodegeneration · doi

  In this review, by connecting molecular insights with systems-level neuroimaging, we elucidate the molecu- lar architecture of tau filaments and possible propaga- tion mechanisms, including the cryo-EM structural conformation of tau isoforms, aberrant intraneuronal redistribution, and transsynaptic spreading patterns. Tau PET has shown great potential in clinical utility and enables the in vivo detection of tau. Second-generation tau tracers, including 18F-PI-2620 and 18F-APN-1607, exhibit enhanced specificity for detecting topographical tau distribution patterns in PSP, enabling improved dis- crimination of overlapping disorders. Emerging clinical trials demonstrate the utility of tau PET for monitoring disease progression and evaluating therapeutic effects. Despite significant advances, key challenges remain in the application of tau-PET imaging for PSP. First, the sensitivity of current tracers to early subcortical tau pathology needs to be further evaluated, especially in prodromal stages or PSP-non-RS subtypes. Second, the Dong et al. Translational Neurodegeneration (2026) 15:14 Page 11 of 13 discrepancy between cortical tau PET signals and cog- nitive dysfunction may reflect either methodological limitations (e.g., reference region selection) or intrin- sic limitations of the current tracers. Third, the extent of off-target binding of second-generation tau tracers to neuromelanin, microhemorrhages, TMEM106B in the choroid plexus, Aβ or other pathological proteins requires careful evaluation. Addressing these gaps will require the development of tau tracers with higher affinity for 4R-tau, standard- ized quantification methods accounting for PSP-spe- cific reference regions, and potential off-target binding evaluation. Furthermore, the integration of tau PET with complementary fluid biomarkers and multimodal neuroimaging will assist in the multidimensional diag- nosis of PSP with early detection and intervention.

  generalstated in future workevidence 5/5
  Keywords: tracers second neuroimaging including patterns potential clinical utility detection generation current early limitations reference target
• Nuclear Speckle Protein SRRM2 Co-localized with Pathological Tau (pTauS396) in Neuronal and Glial Cells in Progressive Supranuclear Palsy (2026) · ACTA HISTOCHEMICA ET CYTOCHEMICA · doi

  Whether SRRM2 mislocalization contributes to disease pathogenesis or represents a conse- quence of tau aggregation remains to be determined. Lastly, the functional consequences of SRRM2 mislocalization were not assessed, leaving its role in RNA processing disruption and neurodegeneration an open question. Nonetheless, the spatial profiling of SRRM2 in PSP high- lights its potential as a marker of tau-associated cellular dysfunction and provides a basis for further investigation into its mechanistic role in neurodegenerative tauopathies. Technical challenges with available antibodies in formalin-fixed paraffin-embedded (FFPE) tis- sue precluded successful co-staining with specific astro- cytic markers such as GFAP; thus, future studies utilizing alternative tissue preparations or optimized markers are warranted to confirm these cell-type assignments.

  generalstated in inline gapsevidence 5/5
  Keywords: srrm mislocalization role markers whether contributes disease pathogenesis represents conse quence aggregation remains determined lastly
• Nuclear Speckle Protein SRRM2 Co-localized with Pathological Tau (pTauS396) in Neuronal and Glial Cells in Progressive Supranuclear Palsy (2026) · ACTA HISTOCHEMICA ET CYTOCHEMICA · doi

  Future studies should investigate the co-localization of SRRM2 and pathological tau in other brain regions. - Future studies should examine the functional implications of SRRM2 mislocalization in PSP. - Future studies should develop therapeutic strategies targeting tau pathology in PSP.

  generalstated in cells future researchevidence 5/5
  Keywords: future studies investigate co-localization srrm2 pathological tau other
• Multivalent Tau-Fyn interactions cooperatively arrest postsynaptic density condensate dynamics (2026) · bioRxiv · doi

  Tau-Fyn signaling at postsynaptic sites is implicated in synaptic dysfunction and neuronal hyperexcitability in Alzheimer's disease and related tauopathies, yet the molecular mechanisms by which Tau-Fyn interactions influence postsynaptic signaling assemblies remain poorly understood.

  generalstated in abstractevidence 2/5
  Keywords: signaling postsynaptic sites implicated synaptic dysfunction neuronal hyperexcitability alzheimer disease related tauopathies molecular mechanisms interactions

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