Acta Neuropathologica Communications最新文献

{"title":"Refining prognostic stratification of atypical meningiomas: significance of chromosome 1p deletion and brain invasion.","authors":"Greta Zanconato, Gonzalo Hernandez Gamero, Andrea Mafficini, Serena Pedron, Davide Mulone, Sara Alberti, Maria Caffo, Valeria Barresi","doi":"10.1186/s40478-025-01973-6","DOIUrl":"10.1186/s40478-025-01973-6","url":null,"abstract":"<p><p>Atypical meningiomas display heterogeneous clinical outcomes, necessitating prognostic markers to identify cases that would benefit of adjuvant treatment. This study investigated the prognostic value of chromosome 1p deletion, assessed by fluorescent in situ hybridization (FISH), in a cohort of 98 primary atypical meningiomas. The accuracy of FISH was validated by comparison with next-generation sequencing (NGS) results. Chromosome 1p deletion was significantly associated with parafalcine/tentorial location, high mitotic index, recurrence, and shorter recurrence-free survival (RFS). Multivariate analysis confirmed the presence of 1p deletion as an independent prognostic factor for shorter RFS. The study also evaluated the immunohistochemical expression of MCM2 and ACADL, which were more frequent in 1p-deleted tumors, but could not reliably predict 1p status. Brain-invasive otherwise benign (BIOB) meningiomas had significantly lower rates of 1p deletion, MCM2 expression, and recurrence, than mitotically active atypical meningiomas. However, recurring BIOB meningiomas showed higher frequencies of MCM2 expression, spontaneous necrosis, and 1p deletion, suggesting that these features may identify BIOB cases with a higher recurrence risk. In conclusion, FISH-detected 1p deletion is a reliable prognostic marker for atypical meningiomas, and its assessment, along with histopathological and immunohistochemical features, can refine the prognostic stratification of these tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"50"},"PeriodicalIF":6.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinomenine alleviates neuroinflammation in chronic cerebral hypoperfusion by promoting M2 microglial polarization and inhibiting neuronal pyroptosis via exosomal miRNA-223-3p.","authors":"Qu Yang, Qi Chen, Kai-Bing Zhang, Yu Liu, Jia-Cheng Zheng, Dong-Xia Hu, Jun Luo","doi":"10.1186/s40478-025-01950-z","DOIUrl":"10.1186/s40478-025-01950-z","url":null,"abstract":"<p><p>Chronic cerebral hypoperfusion (CCH) is a major contributor to vascular dementia, with neuroinflammation playing a central role in its pathogenesis. Sinomenine (SINO), a natural alkaloid derived from traditional Chinese medicine, has shown significant anti-inflammatory and neuroprotective properties. However, its efficacy and mechanism of action in CCH remain unclear. In this study, we established a CCH rat model through bilateral common carotid artery occlusion and administered 10 mg/kg of SINO daily. Behavioral tests demonstrated that SINO significantly improved cognitive and memory functions in CCH rats. Histological analysis revealed that SINO effectively reduced neuroinflammation and damage in the hippocampal CA1, CA3, and DG regions. Mechanistically, SINO promoted microglial polarization from the M1 to M2 phenotype, markedly inhibiting the release of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Further exploration of its neuroprotective mechanism showed that exosomes from SINO-treated microglia were enriched with miRNA-223-3p, which suppressed NLRP3-mediated pyroptosis in neurons. While our findings highlight the therapeutic potential of SINO, further studies are needed to validate its safety and efficacy in diverse populations and chronic settings. In summary, this study not only demonstrates SINO's regulatory effect on microglial polarization in CCH but also unveils a novel neuroprotective mechanism through exosomal miRNA-223-3p delivery, providing a solid theoretical foundation for SINO's potential as a treatment for CCH.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"48"},"PeriodicalIF":6.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases.","authors":"Kerry Blair, Raquel Martinez-Serra, Philippe Gosset, Sandra M Martín-Guerrero, Gábor M Mórotz, Joseph Atherton, Jacqueline C Mitchell, Andrea Markovinovic, Christopher C J Miller","doi":"10.1186/s40478-025-01964-7","DOIUrl":"10.1186/s40478-025-01964-7","url":null,"abstract":"<p><p>Signaling between the endoplasmic reticulum (ER) and mitochondria regulates many of the seemingly disparate physiological functions that are damaged in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). A number of studies have now demonstrated that ER-mitochondria signaling is perturbed in these diseases and there is evidence that this may be a driving mechanism in disease onset and progression. VAPB and PTPIP51 are ER-mitochondria tethering proteins; VAPB is an ER protein and PTPIP51 is an outer mitochondrial membrane protein and the two proteins interact to enable inter-organelle signaling. The VAPB-PTPIP51 interaction is disrupted in Alzheimer's disease, Parkinson's disease, FTD and ALS. Here we review the roles of VAPB and PTPIP51 in ER-mitochondria signaling and the mechanisms by which neurodegenerative disease insults may disrupt the VAPB-PTPIP51 interaction.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"49"},"PeriodicalIF":6.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating genotype-phenotype correlation of limb-girdle muscular dystrophy R8: association of clinical severity, protein biological function and protein oligomerization.","authors":"Xiongda Liang, Jiameng Si, Hongting Xie, Yuqing Guan, Wanying Lin, Zezhang Lin, Ganwei Zheng, Xiaofeng Wei, Xingbang Xiong, Zhengfei Zhuang, Xuan Shang","doi":"10.1186/s40478-025-01971-8","DOIUrl":"10.1186/s40478-025-01971-8","url":null,"abstract":"<p><p>Limb-girdle muscular dystrophy R8 (LGMD R8) is a hereditary muscle disease caused by biallelic defects in E3 ubiquitinated ligase gene (TRIM32). LGMD R8 is featured by high genetic heterogeneity and phenotypic diversity, most pathogenic variants are missense variants located in the NHL domain, but the genotype-phenotype correlation remains unclear. We hypothesized that various missense variants in NHL domain might have different degrees of impact on the structure and function of the protein, thus resulting in disease variability. Firstly, by analyzing present patients' clinical data, we screen out 4 variants: R394H, D487N, V591M and P619S. Patients homozygous for the aforementioned variants exhibited significant phenotypic variability, including variations in age of onset and age of any walking aid (AWA). Then, bioinformatics analysis, cellular functional experiment and biophysical assay were used to measure the effect of above variants in TRIM32 protein oligomerization and ubiquitination to target substrates. And they revealed distinct differences in the intrinsic E3 ligase activity among various mutant TRIM32 proteins, which corresponded to differences in their oligomerization status. In conclusion, our results showed a correlation between clinical severity, protein function and oligomerization state in patients homozygous for missense variants in NHL domain. It is the first time to reveal a connection between TRIM32 variant with LGMD R8 phenotype and this finding provided valuable reference in predicting disease severity and more precise guidance to affected family on genetic counseling.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"47"},"PeriodicalIF":6.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anlotinib may have a therapeutic effect on papillary craniopharyngiomas without the BRAFv600e mutation.","authors":"Yilamujiang Ainiwan, Haomin Li, Yongjia Zheng, Songtao Wei, Junxiang Peng, Jing Nie, Chaofu Mao, Kunxiang Chen, Siyuan Chen, Ningyuan Liu, Can Li, Yan Chen, Shanqiang Qu, Yunji Wang, Mingfeng Zhou, Jian Mao, Fen Mei, Jingting Chen, Qiancheng Song, Songtao Qi, Jun Pan","doi":"10.1186/s40478-025-01972-7","DOIUrl":"10.1186/s40478-025-01972-7","url":null,"abstract":"<p><strong>Background: </strong>Although successful treatment of papillary craniopharyngiomas (PCPs) with BRAFv600e inhibitors has been reported in clinical trials, studies have shown that approximately 10% of PCPs lack the BRAFv600e mutation and that BRAFv600e inhibitors may not be significantly effective against these tumors. However, no studies have focused specifically on BRAFv600e^- PCPs.</p><p><strong>Methods: </strong>Spatial transcriptome sequencing was performed on calcified PCP tissue to identify novel subtypes of PCP cells. The findings were validated via pathological methods in 51 PCP samples. Primary PCP cells from BRAFv600e^- PCP patients and BRAFv600e⁺ PCP patients were isolated and then injected into the brains of nude mice via stereotactic surgery to establish a stable mouse model of human-originated PCP. Model mice were treated with vemurafenib, a BRAF inhibitor, and anlotinib, an angiogenesis inhibitor. BRAFv600e^-PCP patients were treated with anlotinib in a phase 1 clinical trial. Changes in the tumors of the model mice and patients were monitored via pathological methods, CT and MRI.</p><p><strong>Results: </strong>Most of calcified PCPs were negative for the BRAFv600e mutation, and findings from the mouse model confirmed that vemurafenib may not have a significant therapeutic effect on BRAFv600e^- PCPs. However, the mouse model verified that, anlotinib may have a significant therapeutic effect on BRAFv600e^- PCPs. Two patients with BRAFv600e^- PCPs participated in a phase 1 clinical trial and received anlotinib therapy; their tumors disappeared after 3 months of therapy and did not recur within 24 months follow-up after stopping the treatment.</p><p><strong>Conclusion: </strong>BRAFv600e^- PCPs are characterized by calcification and do not respond to the BRAF inhibitor vemurafenib, and for which the angiogenesis inhibitor anlotinib may have a significant therapeutic effect.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"46"},"PeriodicalIF":6.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of CAR-T cell therapy for NF1/SWN-related nerve sheath tumor treatment.","authors":"Na Tang, Lei Cheng, Jiawei Hao, Beilei Xu, Xi Pan, Xiaofei Wei, Hao Wu, Haoyi Wang","doi":"10.1186/s40478-025-01965-6","DOIUrl":"10.1186/s40478-025-01965-6","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) and schwannomatosis (SWN) are rare genetic disorders with distinct genetic etiologies. Both syndromes are predominantly characterized by the development of multiple benign nerve sheath tumors, which typically arise from cranial/peripheral nerves. The management of NF1/SWN-associated benign nerve sheath tumors pose a substantial clinical challenge. In recent years, immunotherapy has demonstrated significant efficacy in treating various tumors, but its application to NF1/SWN has not been explored. In this study, we first evaluated the feasibility of chimeric antigen receptor (CAR)-T cell therapy for the treatment of benign NF1/SWN-related nerve sheath tumor by analyzing the expression of multiple antigens in 85 tumor samples. Our findings revealed that epidermal growth factor receptor (EGFR/HER1) was highly expressed in most samples, indicating its potential as an ideal target for CAR-T cell therapy. Additionally, TGFβ1 and PDL1, key inhibitory regulators of T cell function within solid tumor microenvironment (TME), were universally overexpressed in these samples, highlighting the immunosuppressive nature of NF1/SWN tumors. To target HER1, we constructed CARs using three distinct scFvs (806, E2 and NEC). All three types of CAR-T cells demonstrated significant tumor-eliminating capability against NF1/SWN tumor cell lines, with 806 CAR-T cells showing the highest efficacy. Considering the immunosuppressive TME, we knocked out TGFBR2 and/or PDCD1 in 806 CAR-T cells using CRISPR/Cas9. Their anti-tumor efficacy was further evaluated using a 3D tumor spheroid model, and the gene-edited 806 CAR-T cells exhibited superior anti-tumor efficacy. In conclusion, we identified HER1 as a target for CAR-T cell therapy in NF1/SWN-related nerve sheath tumors, and developed anti-HER1 CAR-T cells that effectively eliminated NF1/SWN tumor cells, providing a promising therapeutic strategy for patients with these conditions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"45"},"PeriodicalIF":6.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Locus coeruleus tau validates and informs high-resolution MRI in aging and at earliest Alzheimer's pathology stages.","authors":"Alexander T Hary, Smriti Chadha, Nathaniel Mercaldo, Erin-Marie C Smith, André J W van der Kouwe, Bruce Fischl, Christopher Mount, Liana Kozanno, Matthew P Frosch, Jean C Augustinack","doi":"10.1186/s40478-025-01957-6","DOIUrl":"10.1186/s40478-025-01957-6","url":null,"abstract":"<p><p>The locus coeruleus (LC) has been identified as a site that develops phosphorylated tau pathology earlier than cerebral cortex. We present data using high-resolution postmortem MRI and validated tau histopathology in controls and the earliest Braak and Braak (BB) stages (BBI-BBII) in LC. The high-resolution ex vivo MRI provides a 3D volume (quantitative), while the histology reveals tau specificity and severity burden (semi-quantitative). We mapped our highly regionally specific LC data onto high-resolution 3D MRI reconstructions of the same samples used in histology (n = 11). We noted significant structural subatrophy between BB 0 and II (30.0% smaller volumes, p = 0.0381), a trend which primarily affected the rostral-most LC (49.2% smaller average volume, p = 0.0381). We show histopathology data on both the LC and neighboring dorsal raphe caudal (DRc), which were assessed at multiple rostrocaudal levels and mapped with highly sensitive tau severity spatial matrices. We observed significant LC tau accumulation between BB I and II (37.6% increase, p < 0.0001), which may reflect pathology change prior to presumptive cognitive impairment at BB III. Tau pathology was most severe in the middle portion of the LC (11.3% greater compared to rostral LC, p = 0.0289) when including BB III. We noted a significant rostrocaudal gradient of DRc tau severity (58.2% decrease between rostral and caudal DRc, p < 0.0001), suggesting selective regional vulnerabilities of both nuclei. Our study represents a rigorous approach to investigating LC and DRc pathology, having multiple histology sections per sublevel and high-resolution MRI to measure the whole LC, without missing slices in a histological only approach. Taken together, our findings provide novel validated data that demonstrate the tau pathology occurring in the LC and DRc during preclinical AD stages, and alongside spatial reconstructions that will serve as valuable references for in vivo LC imaging.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"44"},"PeriodicalIF":6.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging features and consideration of progression pattern of diffuse hemispheric gliomas, H3 G34-mutant.","authors":"Yuji Kibe, Lushun Chalise, Fumiharu Ohka, Kazuya Motomura, Norimoto Nakahara, Kosuke Aoki, Shoichi Deguchi, Yoshiki Shiba, Kazuhito Takeuchi, Kenichiro Iwami, Junya Yamaguchi, Hiroki Shimizu, Sachi Maeda, Yuhei Takido, Ryo Yamamoto, Yusuke Okuno, Akihiro Sakai, Kennosuke Karube, Ryuta Saito","doi":"10.1186/s40478-025-01945-w","DOIUrl":"10.1186/s40478-025-01945-w","url":null,"abstract":"<p><p>Diffuse hemispheric glioma H3 G34-mutant (DHG) has been identified as a distinct pediatric-type high-grade glioma, according to the World Health Organization (WHO) classification of central nervous system tumors. Widely accepted treatment options include surgery, radiation, and conventional chemotherapy. However, the efficacy of the surgical resection remains unclear. Although there are some reports, a comprehensive understanding of the clinical characteristics, pathogenesis, and outcomes of DHG is insufficient to evaluate the efficacy of maximal tumor resection. We retrospectively analyzed nine cases of DHG, focusing on imaging features and progression patterns. Initial Magnetic Resonance Imaging (MRI) revealed T2/FLAIR high lesions with minimal or no contrast enhancement in all cases. The lesions exhibited T2/FLAIR hyperintensities and focal diffusion restriction in the deep white matter, with most showing high methionine accumulation, suggesting deep white matter infiltration at the time of diagnosis. The extent of white matter infiltration in tumor resection cases was significantly negatively correlated with the extent of resection (EOR). In addition, cases with EOR of 90% or more had significantly longer progression-free survival (PFS) and overall survival (OS). However, achieving an EOR of 90% or more was possible in fewer than half of the cases, primarily in those with relatively limited white matter involvement. Histopathological findings of the tumor obtained by initial resection and autopsy revealed extensive deep white matter infiltration, with one patient demonstrating tumor invasion into the brainstem at death. Our study highlights early deep white matter infiltration of DHGs, complicating surgical resection, and potentially contributing to a poor prognosis. While EOR may influence survival to some extent, residual lesions extensively infiltrate the white matter and eventually invade the brainstem and contralateral brain, thereby contributing to mortality. These findings underscore the challenges of managing DHGs and emphasize the need for further research on effective therapeutic strategies, particularly to understand and target their unique progression patterns.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"43"},"PeriodicalIF":6.2,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism.","authors":"Tyrique Richardson, Xu Hou, Fabienne C Fiesel, Zbigniew K Wszolek, Dennis W Dickson, Wolfdieter Springer","doi":"10.1186/s40478-025-01955-8","DOIUrl":"10.1186/s40478-025-01955-8","url":null,"abstract":"<p><p>The enzyme pair PINK1 and PRKN together orchestrates a cytoprotective mitophagy pathway that selectively tags damaged mitochondria with phospho-serine 65 ubiquitin (pS65-Ub) and directs them for autophagic-lysosomal degradation (mitophagy). We previously demonstrated a significant accumulation of pS65-Ub signals in autopsy brains of sporadic Lewy body disease and Alzheimer's disease cases, which strongly correlated with early tau pathology. In this study, we extended our analysis to a series of pathologically confirmed cases of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) harboring different pathogenic mutations in MAPT, the gene encoding tau. We assessed the morphology, levels, and distribution of the mitophagy tag pS65-Ub in several affected brain regions and hippocampal subregions of these cases. While tau pathological burden was similarly increased across all FTDP-17 cases, pS65-Ub immunopositive signals were strongly accumulated in P301L cases and only weakly present in N279K cases. In the hippocampus of both mutation groups, the density of pS65-Ub positive cells was overall the greatest in the dentate gyrus followed by the subiculum, CA1, and CA2/3, with the CA4 showing only minimal presence. Notably, positive cells in the subiculum carried greater numbers and particularly vacuolar pS65-Ub structures, while cells in the dentate gyrus mostly contained fewer and rather granular pS65-Ub inclusions. Single cell analyses revealed differential co-localization of pS65-Ub with mitochondria, autophagosomes, and lysosomes in these two regions. Together, our study demonstrates distinct mitophagy alteration in different FTDP-17 MAPT cases and hint at selective organelle failure in the hippocampal subregions that was associated with the P301L mutation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"41"},"PeriodicalIF":6.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging the gap: investigating the role of phosphorylation at the serine 129 site of α-synuclein in VAPB-PTPIP51 interactions.","authors":"Weijin Liu, Yongquan Lu, Jia Liu, Yan Yu, Hui Yang","doi":"10.1186/s40478-025-01949-6","DOIUrl":"10.1186/s40478-025-01949-6","url":null,"abstract":"<p><p>Parkinson's Disease (PD) is characterized by the aggregation and accumulation of α-synuclein (α-syn), along with abnormally high levels of α-syn phosphorylation at the serine 129 site (pSer 129 α-syn, p-α-syn). However, the mechanisms underlying the extensive phosphorylation at the serine 129 site in the pathogenesis of PD, as well as the role of p-α-syn in the process, remain unclear. Furthermore, though α-syn could bind to VAPB and loosen Endoplasmic Reticulum (ER)-mitochondria associations by disrupting VAPB-PTPIP51 tethers, whether and how the phosphorylation of α-syn at the serine 129 site regulates VAPB-PTPIP51 interactions, remains unclear. Herein, Co-Immunoprecipitation and Mass Spectrometry (CO-IP/MS) studies were preformed to identify and compare the Protein-Protein Interactions (PPIs) of phosphorylated and total α-syn in the midbrains of Thy1-SNCA transgenic mice. We further performed CO-IP and Molecular Dynamics (MD) simulation assays to confirm the influence of α-syn phosphorylation on the aforementioned interactions. Additionally, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to annotate the functional features of the common interacting proteins of p-α-syn and VAPB. The potential downstream proteins were further verified via CO-IP. According to the CO-IP and MD results, phosphorylation at the serine 129 site of α-syn increased VAPB-PTPIP51 interactions, and α-syn interacted directly with PTPIP51. Furthermore, functional and pathway enrichment analyses revealed that the common interacting proteins of p-α-syn and VAPB were significantly involved in protein binding, metal ion binding, structural constituent of the cytoskeleton, the intermediate filament cytoskeleton, and microtubule organization processes. Moreover, our findings confirmed the interactions of potential downstream target proteins (CLTC, CAMK2A, ATP1A3, and TUBB4B) with p-α-syn and VAPB. These findings collectively elucidate the structural underpinnings of serine 129 phosphorylation regulates the interaction between α-syn and both VAPB and PTPIP51. We hope that these findings will provide valuable insights into the role and regulatory mechanisms of serine 129 phosphorylation in the pathogenesis of pertinent diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"40"},"PeriodicalIF":6.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}