Acta Neuropathologica Communications最新文献

{"title":"Targeting NAD + biosynthesis suppresses TGF-β1/Smads/RAB26 axis and potentiates cisplatin cytotoxicity in non-small cell lung cancer brain metastasis.","authors":"Liyun Zhou, Zhiying Li, Shengli Zhou, Bin Wang, Zhen Liang, Sen Hu, Hang Zhang, Lin Duan, Dongxu Zhao, Luyao Cheng, Hang Ren, Hiroaki Wakimoto, Ming Li","doi":"10.1186/s40478-025-01967-4","DOIUrl":"10.1186/s40478-025-01967-4","url":null,"abstract":"<p><p>Nicotinamide adenine dinucleotide (NAD⁺) plays an important role in tumor progression, but its role in non-small cell lung cancer with brain metastasis (NSCLC BM) remains unclear. Herein, we investigated NAD⁺ biosynthesis targeting as a new therapeutic strategy for NSCLC BM. Therapeutic activity of nicotinamide phosphoribosyl transferase (NAMPT) inhibitors was evaluated in mouse models of NSCLC BM and using various assays such as NAD⁺ quantitation, cell viability, and apoptosis assays. To explore impact on downstream signaling, RNA sequencing was used in NAMPT inhibitor-treated and control cells, followed by validation with genetic knockdown, western blot and qRT-PCR. Expression of NAMPT and downstream proteins in human NSCLC BM and its association with patient prognosis were examined. Finally, combination of NAMPT inhibitor and cisplatin was tested in vivo. Systemic treatment with NAMPT inhibitors demonstrated intracranial activity in an NSCLC BM model. NAMPT inhibitors decreased cellular NAD levels and suppressed proliferation and invasion, and induced apoptosis in NSCLC cells. Supplementation with NAD⁺ precursor NMN rescued these NAMPT inhibitor effects. Mechanistically, disruption of NAMPT-mediated NAD⁺ biosynthesis suppressed TGF-β1/Smads/RAB26 signaling, leading to inhibition of NSCLC cells. Expression of NAMPT/TGF-β1/Smads/RAB26 axis proteins was upregulated in NSCLC BM tissues and correlated with poor prognosis. Combining NAMPT inhibitors with cisplatin further extended the survival of NSCLC BM-bearing mice. Targeting NAD⁺ biosynthesis provides a new therapeutic strategy for NSCLC BM and can be effectively combined with cisplatin. Our studies identified the TGF-β1/Smads/RAB26 signaling downstream of NAMPT, which was targeted by NAMPT inhibition to mediate anti-cancer effects.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"56"},"PeriodicalIF":6.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603379","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":"Granular cytoplasmic inclusions in astrocytes and microglial activation in the fetal brain of pigtail macaques in response to maternal viral infection.","authors":"Raj P Kapur, Andrew E Vo, Amanda Li, Miranda Li, Jeff Munson, Hazel Huang, Briana Del Rosario, Orlando Cervantes, Hong Zhao, Ashley Vong, Gygeria Manuel, Edmunda Li, Monica Devaraju, Xuemei Deng, Audrey Baldessari, W McIntyre Durning, Solomon Wangari, Brenna Menz, Audrey Germond, Chris English, Michelle Coleman, Austyn Orvis, Sidney Sun, Ed Parker, Sandra Juul, Brendy Fountaine, Lakshmi Rajagopal, Kristina M Adams Waldorf","doi":"10.1186/s40478-025-01970-9","DOIUrl":"10.1186/s40478-025-01970-9","url":null,"abstract":"<p><p>The fetal origins of neuropsychiatric disorders are poorly understood but have been linked to viral or inflammatory injury of the developing brain. The fetal white matter is particularly susceptible to injury as myelination, axonal growth, and deep white matter tracts become established. We have used the pigtail macaque (Macaca nemestrina) to study the maternal and fetal effects of influenza A virus (FLUAV) and Zika virus (ZIKV) infection during pregnancy, in cohorts with different time intervals between inoculation and delivery. We observed a striking histopathological alteration in a subset of astrocytes which contained granular cytoplasmic inclusions (\"inclusion cells\", ICs) within a specific region of the deep cerebral white matter in the fetal brains from specific FLUAV and ZIKV cohorts. Immunohistochemical and ultrastructural characteristics of ICs indicated that they are astrocytes (GFAP+) undergoing autophagocytosis (p62+) with activated lysosomes (LAMP1+, LAMP2+) and reactive changes in neighboring microglia. There was also a positive correlation between the number of ICs and LAMP1 or LAMP2 immunoreactivity in the fetal brain (LAMP1: rho 0.66; LAMP2: rho 0.54, p < 0.001 for both). Interestingly, ICs were significantly more prevalent in the 5-day FLUAV cohort and the 21-day intermediate ZIKV cohort than in controls (p < 0.005 and p = 0.04, respectively), but this relationship was not apparent in the ZIKV cohort with a shorter (2-3 days) or longer (months) time course. Virologic and immunologic assays indicated that the appearance of these cells was not linked with fetal brain infection. ICs were not observed in a macaque model of perinatal hypoxic ischemic encephalopathy. These alterations in fetal white matter are pathologically abnormal and may represent a transient neuropathologic finding that signifies a subtle brain injury in the fetus after maternal viral infection.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"55"},"PeriodicalIF":6.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603375","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":"DNA methylation profiling from cerebrospinal fluid as a diagnostic tool for pineoblastoma.","authors":"Celeste Antonacci, Luana Abballe, Sara Patrizi, Lucia Pedace, Sabina Barresi, Isabella Giovannoni, Chantal Tancredi, Flavia Vinciarelli, Giacomina Megaro, Andrea Carai, Sabrina Rossi, Franco Locatelli, Angela Mastronuzzi, Evelina Miele","doi":"10.1186/s40478-025-01960-x","DOIUrl":"10.1186/s40478-025-01960-x","url":null,"abstract":"<p><p>Pineoblastoma is a rare and aggressive malignancy that often affects pediatric populations. Accurate diagnosis is challenging due to histological overlap with other central nervous system tumors and limited molecular data. DNA methylation profiling and analysis of circulating tumor DNA (derived from both cell dissemination as well as cell-free- cfDNA) in cerebrospinal fluid (CSF) are emerging tools for precise tumor classification, in the field of pediatric central nervous system tumors. Here, we report a challenging case of a 17-year-old refugee girl with a previous diagnosis of a primitive neuroectodermal tumor. Formalin-fixed, paraffin-embedded tissue was not available for histopathological re-evaluation. However, the methylation profiling of low amount of CSF-derived DNA classified the tumor as \"pineoblastoma, subtype miRNA processing altered 1, subclass A,\" enabling patient management. The diagnosis was later confirmed through tissue-based DNA methylation analysis of a secondary lesion, demonstrating that the epigenetic signature faithfully reflected tumor features. This case report highlights the potential of CSF-based DNA methylation profiling as a minimally invasive yet accurate diagnostic tool for pediatric CNS tumors. The concordance between CSF and tissue profiling supports the integration of liquid biopsy into diagnostic workflows, allowing for earlier diagnosis and personalized treatment strategies. However, more studies are needed to demonstrate the reliability of our approach in other CNS malignancies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"52"},"PeriodicalIF":6.2,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584125","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":"Correlative light and electron microscopy imaging of proteinaceous deposits in cell cultures and brain tissues.","authors":"Peizhou Jiang, Dennis W Dickson","doi":"10.1186/s40478-025-01969-2","DOIUrl":"10.1186/s40478-025-01969-2","url":null,"abstract":"<p><p>Identifying protein deposits and associated components is crucial for understanding the pathogenesis of neurodegenerative disorders with intracellular or extracellular deposits. Correlative light and electron microscopy (CLEM) has emerged as a powerful tool to accurately study tissue and cellular pathology by examination of the same target at both microstructural and ultrastructural levels. However, the technical challenges with CLEM have limited its application to neuropathology. Here, we developed a simplified efficient CLEM method and applied it to a cell model that produces a high proportion of α-synuclein (αS) inclusions with immunopositivity to phosphorylated αS and the synaptic vesicle marker SV2A and synaptophysin. This approach incorporates modifications in sample processing and innovative fiducial marking techniques, which enhance antigen preservation and improve target registration, respectively. These advancements achieve an optimal balance in sensitivity, accuracy, efficiency, and cost-effectiveness compared to current CLEM methods employing different strategies. Using this method, we identified and analyzed αS inclusions in cell cultures, as well as various pathological protein deposits in postmortem brain tissues from individuals with a range of neurodegenerative disorders. Our findings replicate recently reported new features of αS pathology and also reveal unrecognized a variety forms of small αS inclusions in human brain, which provide valuable insights into mechanisms underlying Lewy-related pathology. Application of this enhanced CLEM method is a powerful tool in research on neurodegenerative disorders, including αS-opathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"53"},"PeriodicalIF":6.2,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584119","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":"Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.","authors":"Joy Mitra, Manohar Kodavati, Prakash Dharmalingam, Erika N Guerrero, K S Rao, Ralph M Garruto, Muralidhar L Hegde","doi":"10.1186/s40478-025-01962-9","DOIUrl":"10.1186/s40478-025-01962-9","url":null,"abstract":"<p><p>TDP-43 mislocalization and aggregation are key pathological features of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD). However, existing transgenic hTDP-43 WT or ∆NLS-overexpression animal models primarily focus on late-stage TDP-43 proteinopathy. To complement these models and to study the early-stage motor neuron-specific pathology during pre-symptomatic phases of disease progression, we generated a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43∆NLS variant of mouse Tdp-43. This variant is expressed either in the whole body (WB) or specifically in the motor neurons (MNs) in two distinct models. These mice exhibit loss of nuclear Tdp-43, with concomitant cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation, and associated cellular senescence. Notably, unlike WT Tdp-43, which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43∆NLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mouse brain. The mutant mice also exhibit myogenic degeneration in hindlimb soleus muscles and distinct motor deficits, consistent with the characteristics of motor neuron disease (MND). Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43∆NLS mutant, independent of Tdp-43 overexpression or other confounding factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to characterize the early-stage progression of MND further and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"54"},"PeriodicalIF":6.2,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584133","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":"Antagonizing Il10 and Il4 signaling via intracerebral decoy receptor expression attenuates Aβ accumulation.","authors":"Emily J Koller, Karen N McFarland, Conner Angelle, John Howard, Danny Ryu, Kristy D Dillon, Aya Erquizi, Mihir Beheray, Elsa Gonzalez De La Cruz, Pedro E Cruz, Jada Lewis, Todd E Golde, Yona Levites, Paramita Chakrabarty","doi":"10.1186/s40478-025-01968-3","DOIUrl":"10.1186/s40478-025-01968-3","url":null,"abstract":"<p><p>Multiple lines of evidence indicate that immune signaling can impact the pathological progression in Alzheimer's disease (AD), including amyloid deposition, tau aggregation, synaptic pathology and neurodegenerative trajectory. In earlier studies, we reported that intracerebral expression of the anti-inflammatory cytokines, Interleukin-10 (Il10) and Interleukin-4 (Il4), increased amyloid β (Aβ) burden in TgCRND8 mice, a preclinical model of AD-type amyloidosis. As both Interleukin-10 receptor (IL10R) and Interleukin-4 receptor (IL4R) are upregulated in an age-progressive manner in rodent models of AD and in specific regions of human AD brains, we hypothesized that a decoy receptor strategy specifically targeting Il10 and Il4 signaling could have a disease-modifying effect. We derivatized the ectodomains of mouse Il10R (sIl10R) and mouse Il4R (sIl4R) into corresponding recombinant solubilized receptor forms and delivered these intracranially into neonatal TgCRND8 mice or hippocampally into adult TgCRND8 mice with pre-existing Aβ deposits. AAV-mediated expression of sIl10R and sIl4R robustly attenuated Aβ burden in TgCRND8 mice when expressed neonatally while in the hippocampus injection cohort, AAV-sIl4R, but not sIl10R, reduced Aβ burden. sIl10R and sIl4R had opposing effects on microglial and astrocyte proliferation, with sIl10R generally reducing gliosis. RNAseq analysis showed that sIl10R likely acts as a microglial immune checkpoint inhibitor while both sIl10R and sIl4R expression show unexpected impacts on genes related to circadian rhythm. Notably, neither Il10 nor sIl10R expression altered tau pathology in two tau transgenic models, despite robust expression and impacts on glial proliferation. Together, these data reveal that decoy receptor mediated targeting of physiological Il10 or Il4 signaling can beneficially impact amyloid deposition and thus represent novel immunomodulatory approaches for AD therapy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"51"},"PeriodicalIF":6.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583956","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":"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}