Frontiers in Molecular Neuroscience最新文献

{"title":"Engineering exosomes in the treatment of sensorineural hearing loss: from basic research to clinical applications.","authors":"Siqi Wang, Juanjuan Li, Bingxing Yang, Mengdi Li, Man Yu, Peng Zhang, Suwen Bai, Xianhai Zeng","doi":"10.3389/fnmol.2026.1886218","DOIUrl":"https://doi.org/10.3389/fnmol.2026.1886218","url":null,"abstract":"<p><p>Engineered exosomes demonstrate good biocompatibility, barrier-crossing ability, and programmable drug-loading capacity. Recently, they have steadily emerged as a promising area of study for precision intervention in sensorineural hearing loss. This review focuses on numerous main topics, including the selection of exosome sources and donor-cell pretreatment techniques, surface targeting strategies, therapeutic cargo loading methods, the mechanisms by which exosomes cross the blood-labyrinth barrier, and recent advancements in research on the role of exosomes in hair cell protection, spiral ganglion neuron protection, supporting-cell plasticity, and cochlear microenvironment remodeling. This review also examines the key challenges in the clinical translation of exosomes. It comprehensively reviews direct cochlear exosome evidence for hair cell protection and auditory protection, separating these results from indirect non-cochlear exosome evidence and theoretical engineering approaches for spiral ganglion neuron protection, supporting-cell-mediated regeneration-related mechanisms, and cochlear neurovascular microenvironment remodeling. In addition to outlining a framework that combines targeted delivery and functional regulation for sensorineural hearing loss, this review highlights the hearing-protective potential of engineered exosomes in preclinical models and requires further experimental validation. Despite the positive outlook, there are still notable issues with the durability of therapeutic effects, mechanistic clarity, and clinical translatability. Future studies should prioritize standardization of extracellular vesicle reporting, dose reproducibility, clinically relevant models, and long-term functional outcomes.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1886218"},"PeriodicalIF":4.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13542686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.","authors":"Qiaoqiao Cui, Ke Zheng, Qiyun Liu, Lizhen Wang, Yixin Liu, Ruifang Bai, Wei Zhang, Junhong Guo, Xueli Chang, Juan Wang","doi":"10.3389/fnmol.2026.1921079","DOIUrl":"10.3389/fnmol.2026.1921079","url":null,"abstract":"<p><p>Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1921079"},"PeriodicalIF":4.4,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Molecular mechanisms of mental disorders: the contribution of genetic and environmental factors.","authors":"Martina Di Bartolomeo, Claudio D'Addario","doi":"10.3389/fnmol.2026.1937671","DOIUrl":"10.3389/fnmol.2026.1937671","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1937671"},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation in medulloblastoma: from tumor heterogeneity to diagnostic, prognostic, and translational applications.","authors":"Xinling Zhang, Lailing Du, Kewei Tian, Lening Chen, Xiaoping Li","doi":"10.3389/fnmol.2026.1909580","DOIUrl":"10.3389/fnmol.2026.1909580","url":null,"abstract":"<p><p>Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Epigenetic dysregulation, particularly in Group 3 and Group 4 tumors, is a major driver of tumorigenesis despite relatively few recurrent driver mutations. DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs orchestrate aberrant transcriptional programs governing tumor initiation, progression, and cellular identity. Single-cell and multi-omic studies have revealed epigenetic heterogeneity, cellular plasticity, and microenvironmental interactions underlying therapeutic resistance. Epigenetic alterations provide valuable diagnostic and prognostic biomarkers. DNA methylation profiling is the gold standard for molecular classification, while epigenetic signatures and cerebrospinal fluid circulating tumor DNA support precision diagnosis and disease monitoring. This review integrates recent advances in MB epigenetics into a framework linking cellular plasticity and the tumor microenvironment to biomarker-driven precision therapies. Several comprehensive reviews have summarized the epigenetic landscape of medulloblastoma, focusing primarily on DNA methylation, histone modifications, chromatin remodeling, and subgroup-specific epigenetic alterations. While these studies have substantially advanced our understanding of epigenetic mechanisms, the rapid emergence of single-cell sequencing, spatial transcriptomics, multi-omic integration, and three-dimensional chromatin mapping has reshaped the current view of medulloblastoma biology. These technologies provide unprecedented resolution for dissecting intratumoral heterogeneity, developmental trajectories, and dynamic epigenetic regulation not fully addressed in earlier reviews. In this review, we integrate these recent advances into a unified framework connecting classical epigenetic mechanisms with emerging multidimensional epigenomic technologies. We discuss how these insights facilitate biomarker discovery, improve molecular classification, and accelerate precision epigenetic therapies, highlighting future directions for translational research.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1909580"},"PeriodicalIF":4.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diet-gut microbiota-immune-brain interactions in aging: mechanistic pathways and clinical implications.","authors":"Maha A Jarfan, Karani Santhanakrishnan Vimaleswaran, Anisha Wijeyesekera","doi":"10.3389/fnmol.2026.1847644","DOIUrl":"10.3389/fnmol.2026.1847644","url":null,"abstract":"<p><p>With rising life expectancy and global population aging, cognitive decline has become a major and growing public health challenge. Advances in nutritional neuroscience highlight the gut microbiota-immune-brain axis as a key biological pathway through which diet may influence cognitive function during aging. The gut microbiota, a metabolically active ecosystem, responds dynamically to habitual dietary patterns and produces bioactive metabolites capable of modulating immune signaling, neuroinflammation, and neuronal function. Diets rich in microbiota-modulating foods (e.g., dietary fiber, polyphenols, prebiotics, and probiotics) promote beneficial microbial communities. These communities support short-chain fatty acid production, maintain intestinal barrier integrity, and regulate systemic immune responses, processes increasingly associated with cognitive resilience in aging populations. In contrast, Western-style dietary patterns characterized by high intakes of saturated fats and refined sugars are linked to microbial dysbiosis, impaired gut barrier function, metabolic endotoxemia, and chronic low-grade inflammation, which may contribute to neuroinflammatory pathways involved in cognitive decline. This narrative review synthesizes evidence from observational studies, dietary intervention trials, and mechanistic animal models to examine how diet-driven alterations in gut microbiota composition and microbial metabolites interact with and modulate immune pathways to influence brain function in aging populations. Although emerging evidence supports the biological plausibility of this axis in cognitive health, current evidence remains constrained by methodological heterogeneity, short intervention durations, limited functional insight, and substantial inter-individual variability in microbiota responsiveness. In particular, much of the mechanistic understanding derives from preclinical research, while human evidence remains largely associative and insufficient to establish causal pathways. Future research should integrate longitudinal cohort designs, harmonized cognitive assessment tools, and repeated profiling of microbial and host metabolites to clarify the functional and causal links between diet, microbial metabolism, immune regulation, and brain aging. A more integrated understanding of these interactions may help inform targeted, microbiome-informed nutritional strategies for supporting healthy cognitive aging, while maintaining appropriate caution in clinical interpretation.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1847644"},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ERK MAPK pathway in mesenchymal glioblastoma: tumorigenesis, microenvironmental reprogramming, and the therapeutic promise of RAS(ON) multi-selective inhibition.","authors":"Uma M Basole, Mary M Fitzpatric, Joseph Donohoe, Shashank Obulasetti, William Snider, Emily Haugen, Damir Garcia, Ana Gonzalez-Manteiga, Mathieu Sertorio, Marc Oria","doi":"10.3389/fnmol.2026.1857885","DOIUrl":"10.3389/fnmol.2026.1857885","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains one of the most lethal malignancies in adults, with a median survival of 15 months under the current standard of care. The lack of effective targeted therapies is a critical gap, particularly for the mesenchymal subtype of glioblastoma (MES-GBM), which accounts for up to 49% of GBM cases and carries the worst prognosis. Although direct RAS mutations are rare in GBM, mutations in upstream ERK MAPK pathway regulators such as loss-of-function of neurofibromin 1 (<i>NF1</i>) and gain-of-function mutations in epidermal growth factor receptor (<i>EGFR</i>) are highly prevalent in MES-GBM and drive constitutive pathway hyperactivation, chemoresistance, and aggressive tumor behavior. These mutations render the ERK MAPK pathway a compelling, yet underexplored, therapeutic target in GBM. RAS(ON) multi-selective inhibitors, which act upstream by blocking active RAS-GTP across multiple isoforms and mutations, represent a new therapeutic opportunity. Daraxonrasib (RMC-6236), a potent RAS(ON) multi-selective inhibitor currently in Phase III clinical trials for pancreatic cancer, has demonstrated blood-brain barrier (BBB) penetrance in non-GBM brain metastasis models, broad efficacy across RAS-driven cancers, and a favorable tolerability profile in clinical studies. As daraxonrasib targets active RAS regardless of mutation status, it is mechanistically suited for <i>NF1</i>-mutant GBM, in which RAS itself is wild-type but constitutively activated. Beyond direct tumor cell effects, hyperactive RAS signaling in GBM drives pro-tumoral reprogramming of microglia and tumor-associated macrophages (TAMs), creating an immunosuppressive microenvironment that further promotes MES-GBM transition and treatment resistance. RAS(ON) inhibition therefore holds potential to simultaneously suppress tumor proliferation and remodel the tumor microenvironment (TME) toward an anti-tumor state. In this review, we discuss the potential effect of daraxonrasib as an emerging targeted therapeutic candidate in MES-GBM, highlighting the need of further research and clinical evaluation to better determine its therapeutic efficacy dedicated GBM preclinical models.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1857885"},"PeriodicalIF":4.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temperature-induced structural changes in thermosensitive transient receptor potential channels (thermoTRPs).","authors":"Lina Ni","doi":"10.3389/fnmol.2026.1911902","DOIUrl":"10.3389/fnmol.2026.1911902","url":null,"abstract":"<p><p>The ability to sense environmental temperature is fundamental to animal survival, physiological homeostasis, and adaptation to changing environments. Animals rely on temperature-responsive molecules to detect changes in environmental and internal temperatures to maintain their thermal homeostasis. Among these molecules, the best-characterized group belongs to the transient receptor potential (TRP) channel superfamily, commonly referred to as thermoTRPs. ThermoTRPs have been extensively studied and are well established as thermoreceptors. In recent years, cryo-electron microscopy (cryo-EM) has enabled the structural characterization of numerous thermoTRP channels in their closed-state and agonist-induced open state, providing unprecedented insights into their architecture and gating mechanisms. Despite these advances, the molecular mechanisms by which thermoTRPs undergo temperature-induced activation remain poorly understood. This review focuses on six pioneering cryo-EM studies reporting temperature-induced open structures to summarize current structural evidence and discuss potential mechanisms by which temperature drives channel opening in thermoTRPs.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1911902"},"PeriodicalIF":4.4,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depression of synaptic outputs by reduction of Ca²⁺ influx, but not RRP vesicles, becomes evident upon CB2R hyper-expression at cerebellar Purkinje cell terminals.","authors":"Takuma Inoshita, Shin-Ya Kawaguchi","doi":"10.3389/fnmol.2026.1842304","DOIUrl":"10.3389/fnmol.2026.1842304","url":null,"abstract":"<p><p>Synaptic transmission is dynamically regulated by neuromodulators. One well-studied example is cannabinoid receptor type 1 (CB1R)-mediated suppression of neurotransmitter release by reducing presynaptic Ca²⁺ influx. Recently, GPR55 was shown to regulate transmitter release through a mechanism distinct from that of CB1R. However, the presynaptic role of cannabinoid receptor type 2 (CB2R) remains unclear. Here we studied this issue using cerebellar Purkinje cells (PCs), which are known to express both CB2R and GPR55 and amenable to direct patch-clamp recordings from axon terminals. At naïve PC synapses onto target neurons, application of a CB2R agonist did not affect synaptic transmission. The lack of effect was ascribed to minimal endogenous CB2R at distal axon terminals of PCs. Exogenous expression of CB2R enabled suppression of synaptic transmission upon pharmacological activation. Direct voltage-clamp recordings of presynaptic Ca²⁺ current and membrane capacitance changes at boutons demonstrated that CB2R activation reduced presynaptic Ca²⁺ influx without affecting the total amount of readily releasable vesicles, leading to less vesicle exocytosis through lowered release probability. Notably, replacement of two intracellular loops of CB2R with those of GPR55 converted the site of action for synaptic suppression from Ca²⁺ channel inhibition to the reduction of the readily releasable vesicles, as GPR55 does. These findings indicate that, when sufficiently present at axon terminals, CB2R suppresses transmitter release through reduction of Ca²⁺ influx like CB1R, and suggest that intracellular loops of cannabinoid receptors determine whether transmitter release is suppressed through inhibition of presynaptic Ca²⁺ channels or reduction of the readily releasable pool of vesicles.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1842304"},"PeriodicalIF":4.4,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13518366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional signatures of aberrant brain functional network topology in chronic low back pain with lumbar disc herniation.","authors":"Chuanxu Luo, Wanting Liu, Xiaoyi Liu, Han Xu, Hao Gu, Yapan Zhang, Fengchao Shi, Wenhui Li, Siyu Gu","doi":"10.3389/fnmol.2026.1790428","DOIUrl":"10.3389/fnmol.2026.1790428","url":null,"abstract":"<p><strong>Objective: </strong>The central pathophysiology of chronic low back pain (CLBP) secondary to lumbar disc herniation (LDH) remains poorly understood, particularly the link between macroscale brain network dysfunction and its microscale biological underpinnings. This study aimed to bridge this critical gap by integrating resting-state fMRI, graph theory, and imaging transcriptomics.</p><p><strong>Methods: </strong>Resting-state fMRI data were acquired from 62 CLBP patients with LDH and 67 matched healthy controls (HCs). Whole-brain functional networks were constructed for each participant by calculating functional connectivity (FC) between 90 anatomical regions. Graph theoretical analysis was employed to derive global and nodal topological metrics. Group differences were identified and correlated with clinical variables. Crucially, these neuroimaging phenotypes were spatially mapped against the Allen Human Brain Atlas (AHBA) to uncover potential spatial molecular vulnerabilities.</p><p><strong>Results: </strong>At the connectional level, CLBP patients with LDH exhibited widespread hypoconnectivity across sensorimotor, ventral attention, and default mode networks. Further topological analysis revealed a profound focal degradation of hub function in the cingulate cortex, characterized by significantly reduced nodal degree, efficiency, and betweenness centrality (<i>p</i> < 0.001), alongside decreased nodal efficiency in the right supplementary motor area, while global network architecture was preserved. Critically, these deficits in cingulate hub topology were significantly correlated with pain intensity. Imaging transcriptomics linked this focal topological failure to genes enriched for neuroinflammatory and synaptic plasticity pathways.</p><p><strong>Conclusion: </strong>These findings reveal multi-level functional network alterations in CLBP with LDH, linking focal hub failure to potential spatial molecular vulnerabilities associated with neuroinflammation and synaptic remodeling.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1790428"},"PeriodicalIF":4.4,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148827085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the role of EFhd2 protein in modulating tau pathology in a tauopathy mouse model.","authors":"Ahlam S Soliman, Andrew Umstead, Irving E Vega","doi":"10.3389/fnmol.2026.1833887","DOIUrl":"10.3389/fnmol.2026.1833887","url":null,"abstract":"<p><p>Accumulation of abnormally aggregated tau is the main pathological hallmark in tauopathies, including Alzheimer's disease (AD). Increasing evidence suggests that pretangle oligomeric tau aggregates exert neurotoxicity, while neurofibrillary tangles (NFTs) may represent less toxic structures that possibly delay cellular demise. A multitude of <i>in vitro</i> studies have endorsed the low propensity of tau protein to aggregate without an external aggregation inducer. Hence, studying tau-interacting proteins has garnered research attention in the last decade as potential contributors to pathological tau aggregation. We identified EF-Hand Domain Family Member D2 (EFhd2) protein as a tau-associated protein in JNPL3 mouse model and postmortem tauopathies tissues. Recently, we have shown that EFhd2 interacts with tau filaments <i>in vitro</i>, promoting the formation of large unique aggregated structures. Based on these findings and others, we hypothesized that EFhd2 might contribute to the formation of tau aggregates <i>in vivo</i>. To test this hypothesis, we examined the impact of deleting the <i>Efhd2</i> gene on the progressive pathological phenotype and neuropathological changes in Tau _<i>P301L</i> -expressing mice. The results indicated only modest, sex-specific differences in lifespan associated with <i>Efhd2</i> deletion in Tau _<i>P301L</i> mice. Independent of <i>p</i>-values, <i>Efhd2</i> deletion also showed a medium-to-large main effect in reducing cortical pSer422 and PHF1 tau levels in aged mice, consistent with attenuated late-stage tau aggregation. Moreover, <i>Efhd2</i> deletion showed effect-size-based trends toward higher Alz50 staining, suggesting an increase in early pathological tau conformations. These findings indicate that <i>Efhd2</i> deletion is associated with a shift in tau species toward earlier conformational states alongside reduced markers of later-stage aggregation. The observed modest effects do not establish a direct mechanistic role for EFhd2 in tau aggregation <i>in vivo</i>. Rather, they suggest that EFhd2 may function as a modulatory component within a broader protein network influencing tau pathology. Future studies will determine to the extent to which these effects arise from direct modulation of tau aggregation, altered cellular pathways, or interactions within the EFhd2-associated protein network.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"19 ","pages":"1833887"},"PeriodicalIF":4.4,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148827008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}