Whether SRRM2 mislocalization contributes to disease pathogenesis or represents a consequence of tau aggregation remains to be determined

The gap

Evidence profile

Sourced from the future work and inline gaps of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 4 journals. Those papers have been cited 69 times in total.

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.

  generalfuture work
  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.

  generalinline gaps
  Keywords: srrm mislocalization role markers whether contributes disease pathogenesis represents conse quence aggregation remains determined lastly
• The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges (2024) · International Journal of Molecular Sciences · cited 64× · doi

  Although tau aggregation has been studied for almost four decades, the underlying molecular mechanisms remain elusive. Even at high concentrations under typical buffer conditions, wild-type tau proteins do not seem to self-coacervate into liquid droplets or self-assemble into oligomers or fibrils. This is consistent with the initial discovery of tau as a highly soluble, heat-stable protein. There have been many efforts to identify special conditions that induce wild-type tau aggregation. With molecular crowding, LLPS is ob- served, and oligomers may form upon droplet maturation but not fibrils. With hyperphos- phorylation, self-assembly into oligomers is observed but not fibrils. With polyanionic cofac- tors such as heparin or RNA, it is possible to induce LLPS, oligomerization, and fibrillation. In vivo, hyperphosphorylation appears to be the initiation event for aggregation be- cause it dissociates tau from microtubules. It is often thought that tau aggregation is seeded extracellularly by GAGs and intracellularly by RNA. There is increasing evidence to suggest that soluble aggregates (oligomers and protofibrils) are the de facto toxic and seeding species in tauopathies, while fibrillar inclusions are relatively inert and represent secondary pathologies that appear much later. Although tau LLPS appears to occur within cells, whether it leads to oligomer or fibril formation remains to be determined. One of the greatest obstacles in the study of oligomers and protofibrils is the lack of structural investigation tools. They are too heterogeneous to be analyzed as single parti- cles under cryo-EM and too large to be effectively analyzed by solution NMR. The primary tools for investigating their structural features are conformational antibodies recognizing 3D epitopes. Even though cryo-EM has solved the atomic structure of core regions (cov- ering MTBRs and R’) in many types of tau fibrils, the rest of the protein still resides within the “fuzzy coat”. Little is known about the structural roles of fuzzy-coat regions during oligomerization and fibrillation. Although tau is an IDP, there are still transient structural motifs in its native state, called the paperclip conformation (N-terminal and C-terminal regions attracted to the MTBD by electrostatic attraction). Based on the evidence discussed in previous sections, we may provide an “educated guess” about how different regions of tau participate in self-assembly. It seems that electrostatic interactions in the N-terminal half of the protein could drive phase separation and the formation of physiological and pathological oligo- mers. Hyperphosphorylation or polyanion binding could release the N-terminus from the MTBD and promote phase separation and oligomerization. Transient cross-β structures formed in the MTBR may contribute to droplet hardening or oligomer formation, and fur- ther evolution into stable cross-β structures eventually leads to proto

  generalfuture work
  Keywords: oligomers aggregation self fibrils structural regions protein there llps oligomerization formation terminal molecular even conditions
• Tau Protein Aggregation Inhibitors—Therapeutic Strategy for Concurrent Tau and Amyloid Aggregation Inhibition (2026) · Biomedicines · cited 5× · doi

  In the existing literature, tau protein is established as a key molecule that plays significant roles in cytoskeletal organization, intracellular transport, synaptic signaling, and nuclear protection, becoming profoundly maladaptive when disrupted by disease- associated modifications. Developmentally regulated splicing, precise phosphorylation, and dynamic intracellular and extracellular trafficking are essential for normal tau func- tion; however, dysregulation of these processes initiates a cascade of pathological events, including mislocalization, aggregation, liquid–liquid phase separation, and prion-like propagation. Tauopathies are defined not merely by tau accumulation but by distinct, disease-specific filament folds and isoform compositions shaped by post-translational mod- ifications and interacting pathologies. Tau pathology does not act in isolation to produce and sustain neurodegeneration; instead, it is embedded in a self-reinforcing network in- volving amyloid-β, neuroinflammation, mitochondrial dysfunction, and oxidative stress, each of which amplifies tau toxicity and spread. These interdependencies help explain clinical heterogeneity, progressive neurodegeneration, and the limited efficacy of single- target interventions. In this context, effective disease-modifying therapies for AD and related tauopathies require strategies that address tau aggregation and propagation while simultaneously modulating upstream drivers and downstream consequences, including neuronal activity, inflammatory signaling, and cellular proteostasis. Efforts to inhibit tau aggregation have provided a critical proof of concept that di- rectly targeting the structural conversion of tau is biologically feasible and can attenuate pathology in experimental models. However, the limited clinical success of first-generation compounds, such as methylene blue and its derivatives, underscores the challenges posed by inadequate brain exposure, pleiotropic pharmacology, and suboptimal trial design. Natural polyphenols and early small-molecule inhibitors are important for revealing key https://doi.org/10.3390/biomedicines14030522 Biomedicines 2026, 14, 522 16 of 22 mechanistic principles, such as redirecting tau into off-pathway assemblies or enhancing proteostatic clearance. Still, their poor specificity and pharmacokinetic limitations have constrained clinical translation. More recent strategies, including molecular tweezers, oligomer-selective inhibitors, peptide-based approaches, and structure-guided, strain- selective compounds with dual-targeting properties, represent a conceptual shift toward precision modulation of the most toxic tau species. Collectively, these advances suggest that future therapeutic success will depend on improved engagement of brain targets, early intervention, and selective inhibition of pathogenic tau conformers rather than global suppression of aggregation, potentially in combination with complementary approaches that address upstream and downstream disease mechanisms. Author Contributions: Conceptualization, T.G.S. and R.C.C.; methodology, formal analysis, and data curation, T.G.S. and O.D.S.; writing—original draft preparation, T.G.S. and O.D.S.; writing—review and editing, R.C.C.; supervision, R.C.C. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: No new data were created or analyzed in this study. Conflicts of Interest: The authors declare no conflicts of interest.

  generalfuture work
  Keywords: disease aggregation including clinical selective statement molecule intracellular signaling liquid propagation tauopathies pathology neurodegeneration limited

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