Acta Neuropathologica Communications最新文献

{"title":"Characteristics and outcomes of diffuse non-midline gliomas with H3F3A gene mutation in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort study.","authors":"Hirokazu Nakatogawa, Junya Fukai, Hiroshi Kawaji, Nobuhide Hayashi, Ema Yoshioka, Yoshinori Kodama, Kosuke Nakajo, Takehiro Uda, Yoshiki Arakawa, Shigeki Takada, Noriyuki Kijima, Kenichi Ishibashi, Takeshi Okuda, Yukihiko Sonoda, Shiro Ohue, Hideyuki Arita, Masahide Matsuda, Tadateru Fukami, Takahiro Tomita, Akihiro Inoue, Takamune Achiha, Hideki Kashiwagi, Daisuke Kanematsu, Asako Katsuma, Miho Sumida, Tomoko Shofuda, Masayuki Mano, Manabu Kinoshita, Kanji Mori, Chikanori Inenaga, Yonehiro Kanemura","doi":"10.1186/s40478-025-01989-y","DOIUrl":"https://doi.org/10.1186/s40478-025-01989-y","url":null,"abstract":"<p><p>Diffuse gliomas with H3F3A gene mutation such as H3.3 K27M and G34R/V are infrequently found in the cerebral hemisphere. These tumors may be called histone H3 K27M-mutant diffuse non-midline gliomas (NDMG) or H3 G34-mutant diffuse hemispheric gliomas (DHG), respectively. We investigated the clinical, radiological and molecular characteristics and treatment outcomes of patients with H3 K27-mutant NDMG compared with those with H3 G34-mutant DHG. We collected cases of histone H3-mutant diffuse glioma at non-midline location that were enrolled in the Kansai Molecular Diagnosis Network for CNS Tumors. The clinical, radiological and pathological characteristics and DNA methylation were retrospectively analyzed and then compared between cases of NDMG and DHG. We evaluated various factors to examine their effects on overall survival. Included in this study were 16 patients with H3 K27M-mutant NDMG and nine patients with H3 G34R/V-mutant DHG. Patients with NDMG were older than those with DHG (median age: 45 vs. 25 years old). Overall survival times of patients with NDMG were comparable to those of DHG (median overall survival: 20.0 vs. 22.5 months). Female sex, preoperative Karnofsky performance status score ≥ 80 and extensive surgical resection tended be related to better prognoses in the patients with these tumors. H3 K27M-mutant NDMGs were shown to possess similar DNA methylation properties to H3 K27M-mutant DMGs. Diffuse gliomas harboring histone H3 K27M mutation can arise in the cerebral hemisphere in older adults. These findings suggest that H3 K27M-mutant NDMGs show different clinical manifestations to H3 K27M-mutant DMGs and H3 G34R/V-mutant DHGs, despite having similar molecular properties to H3 K27M-mutant DMGs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"77"},"PeriodicalIF":6.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951896","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":"Integrated analysis of molecular and clinical features associated with overall survival in melanoma patients with brain metastasis.","authors":"Swaminathan Kumar, Meredith S Pelster, Merve Hasanov, Renato A Guerrieri, Courtney W Hudgens, Debora A Ledesma, Fuchenchu Wang, Grant M Fischer, Julie M Simon, Lauren E Haydu, Kalman V Katlowitz, Y N Vashisht Gopal, Jennifer L McQuade, Lawrence N Kwong, Jason T Huse, Alexander J Lazar, Michael T Tetzlaff, Jeffrey E Gershenwald, Aron Y Joon, Ken Chen, Ziyi Li, Prahlad T Ram, Sherise D Ferguson, Michael A Davies","doi":"10.1186/s40478-025-01978-1","DOIUrl":"https://doi.org/10.1186/s40478-025-01978-1","url":null,"abstract":"<p><p>Melanoma brain metastases (MBMs) are diagnosed in up to 60% of metastatic melanoma patients. Previous studies have identified clinical factors that correlate with overall survival (OS) after MBM diagnosis. However, molecular and immune features associated with OS are poorly understood. An improved understanding of the molecular and immune correlates of OS could provide insights into MBM patient outcomes and guide therapeutic development. Thus, we analyzed clinical features and outcomes of 74 melanoma patients who underwent surgical resection (via craniotomy) between 1991 and 2015 at our institution with RNA-seq data generated from their MBMs. The median post-operative OS was 8.6 months (range 0.6-146.9). On univariate analysis (UVA), the expression of multiple immune gene signatures was associated with improved OS, including IFN-γ Index, T cell-inflamed and the Expanded Immune Genes. The gene expression signatures of several immune cell types (i.e., T cells, CD8 T cells, cytotoxic lymphocytes, NK cells, monocytes) positively correlated with OS, whereas higher neutrophil gene expression correlated with shorter OS. UVA of clinical features identified low Karnofsky performance score (KPS), elevated serum lactate dehydrogenase (LDH), presence of extracranial metastases (ECMs), and uncontrolled (versus controlled) ECMs as clinical predictors of shorter survival. Multivariate analyses (MVA) were performed with significant clinical factors and all immune features without any redundant highly correlated variables in the model. After backward selection, multivariable coxPH model identified low KPS, low T cell signature, and low monocytic lineage signature as independent predictors of shorter survival. Finally, comparative analysis of MBMs from patients with MBMs only showed that these tumors were characterized by decreased oxidative phosphorylation (OXPHOS) and increased immune infiltration signature versus MBMs from patients with concurrent ECMs. Together these results support the clinical significance of specific immune features of MBMs and suggest their potential use as prognostic biomarkers.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"75"},"PeriodicalIF":6.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11998309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958760","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":"Epitranscriptomic analysis reveals clinical and molecular signatures in glioblastoma.","authors":"Glaucia Maria de Mendonça Fernandes, Wesley Wang, Saman Seyed Ahmadian, Daniel Jones, Jing Peng, Pierre Giglio, Monica Venere, José Javier Otero","doi":"10.1186/s40478-025-01966-5","DOIUrl":"https://doi.org/10.1186/s40478-025-01966-5","url":null,"abstract":"<p><p>This study characterizes the glioblastoma (GB) epitranscriptomic landscape in patient who evolve to progressive disease (PD) or pseudo-progressive disease (psPD). Novel differences in N6-Methyladenosine (m6A) RNA methylation patterns between these groups are identified in the first biopsy. Retrospective data of patients that were eventually deemed to have progressive disease or pseudoprogressive disease was captured from the electronic health record, and RNA from the first resection specimen was utilized to evaluate N6-methyladenosine (m6A) biomarkers from FFPE samples. Molecular analysis of m6A methylation modified RNA employed ACA-based RNase MazF digestion. After Quantitative Normalization with ComBat to mitigate batch effects, we identifed differentially methylated transcripts and gene expression analyses, co-expression networks analyses with WGCNA, and subsequently performed gene set GO and KEGG enrichment analyses. Enrichments for metabolic biological processes and pathways were identified in our differential methylated transcripts and select module eigengene networks highlighted key co-expressed genes intricately tied to distinct phenotypes/traits in patients that would ultimately be deemed PD or psPD. Our study identified key genes and pathways modified by m6A RNA methylation associated with cell metabolism alterations, highlighting the importance of understanding m6A mechanisms leading to the oncometabolite accumulation governing PD versus psPD patients. Furthermore, these data indicate that epitranscriptomal differences between PD versus psPD are detected early in the disease course.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"74"},"PeriodicalIF":6.2,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956224","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":"Transient receptor potential vanilloid 4 blockage attenuates pyroptosis in hippocampus of mice following pilocarpine‑induced status epilepticus.","authors":"Lihan Liu, Yue Wang, Xiaolin Wang, Guowen Zhang, Sha Sha, Rong Zhou, Yimei Du, Chunfeng Wu, Lei Chen","doi":"10.1186/s40478-025-01990-5","DOIUrl":"https://doi.org/10.1186/s40478-025-01990-5","url":null,"abstract":"<p><p>Pyroptosis contributes to the neuronal damage that occurs during epilepsy. Calcium-activated neutral protease (calpain) dissociates cysteinyl aspartate specific proteinase-1 (caspase-1, cas-1) from the cytoskeleton, and the activated cas-1 is responsible for the production of N-terminus of gasdermin D (N-GSDMD), the final executor of pyroptosis. Blocking transient receptor potential vanilloid 4 (TRPV4) can reduce neuronal injury in temporal lobe epilepsy (TLE) model mice. This study investigated the role of TRPV4 in pyroptosis during TLE. In the hippocampus of pilocarpine-induced status epilepticus (PISE) mice, the ratio of inactive calpain 1 protein level to its total protein level (inactive/total calpain 1) significantly decreased, while the ratio of inactive calpain 2 protein level to its total protein level remained unchanged. The protein levels of NLRP3, cleaved cas-1 (c-cas-1), interleukin (IL)-1β, and N-GSDMD increased, with more GSDMD-immunofluorescence-positive (GSDMD⁺) cells and fewer surviving pyramidal neurons observed in the hippocampus of PISE mice. Calpain inhibition with MDL-28170 reversed these changes, except for the elevated NLRP3 levels. Inhibitors targeting NLRP3 (MCC950) and cas-1 (Ac-YVAD-cmk) blocked the increase in c-cas-1, IL-1β, and N-GSDMD levels in the hippocampus of PISE mice. TRPV4 inhibition via HC-067047 increased the inactive/total calpain 1 ratio, decreased NLRP3, c-cas-1, IL-1β, and N-GSDMD protein levels, reduced GSDMD⁺ cells number, and improved pyramidal neuron survival in the hippocampus of PISE mice. Conversely, TRPV4 activation with GSK1016790A decreased the inactive/total calpain 1 ratio, elevated NLRP3, c-cas-1, IL-1β, and N-GSDMD levels, and increased GSDMD⁺ cells number in the hippocampus. In the hippocampus of GSK1016790A-injected mice, the inactive/total calpain 1 ratio was increased by MDL-28170, and c-cas-1, IL-1β, and N-GSDMD protein levels were markedly attenuated by MDL-28170, MCC950, and Ac-YVAD-cmk, respectively. In conclusion, TRPV4 inhibition mitigates pyroptosis in PISE mice by downregulating the calpain 1-NLRP3/cas-1-GSDMD pathway, ultimately reducing neuronal damage.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"73"},"PeriodicalIF":6.2,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951900","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":"Brain alterations and neurologic disorder progression induced by lymphatic dysfunction in the head and neck region.","authors":"Hwayeong Cheon, Dong-Cheol Woo, Seungwoo Cha, Yeon Ji Chae, Inhee Maeng, Seung Jae Oh, Jae Yong Jeon","doi":"10.1186/s40478-025-01953-w","DOIUrl":"10.1186/s40478-025-01953-w","url":null,"abstract":"<p><p>The potential negative impact of lymphatic dysfunction caused by head and neck cancer treatment remains underexplored. Emerging evidence suggests that waste clearance and fluidic balance in the brain are connected to the peripheral lymphatic system in the head and neck region, implying that lymphatic injury in this area could contribute to brain damage. This study aimed to investigate the pathological alterations in the brain induced by peripheral lymphatic dysfunction in the head and neck region using the lymphatic obstruction animal model. An animal model underwent cervical lymph node dissection combined with radiation therapy to simulate the condition with the peripheral lymphatic dysfunction in the head and neck region after cancer treatment. Lymphatic drainage impairment in the head and neck region was associated with significant swelling, disrupted lymphatic drainage, and immune cell infiltration in the white matter. The imaging techniques revealed ventricular enlargement and increased brain water content caused by fluid imbalance leading to significant structural alterations in the brain. Histopathological analysis demonstrated structural brain alterations similar to that of hydrocephalus and cerebral edema, while rotarod tests showed a substantial decline in motor performance. These findings highlight the impact of peripheral lymphatic dysfunction on brain integrity and function. This study provides evidence that brain damage in head and neck cancer patients may be influenced not only by chemotherapy or radiotherapy but also by lymphatic dysfunction caused by surgical interventions. Lymphatic injury in the head and neck region emerges as a potential risk factor for brain damage, underscoring the need for further research into preventive and therapeutic strategies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"72"},"PeriodicalIF":6.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11978131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810086","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":"Tet2 loss and enhanced ciliogenesis suppress α-synuclein pathology.","authors":"Emmanuel Quansah, Naman Vatsa, Elizabeth Ensink, Jaycie Brown, Tyce Cave, Miguel Aguileta, Emily Schulz, Allison Lindquist, Carla Gilliland, Jennifer A Steiner, Martha L Escobar Galvis, Milda Milčiūtė, Michael X Henderson, Patrik Brundin, Lena Brundin, Lee L Marshall, Juozas Gordevicius","doi":"10.1186/s40478-025-01988-z","DOIUrl":"10.1186/s40478-025-01988-z","url":null,"abstract":"<p><p>There are no approved treatments that slow Parkinson's disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late stage PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of α-synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and reduced the accumulation of α-synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of TET2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"71"},"PeriodicalIF":6.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794331","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":"TRPA1 exacerbates selective retinal ganglion cell vulnerability under acute ocular hypertension.","authors":"Wenhan Lu, Yu Wang, Wei Hu, Xinyi Lin, Xiaoyu Tong, Yi Tian, Yuning Chen, Yicong Wang, Yan Xiao, Hongfang Yang, Yi Feng, Xinghuai Sun","doi":"10.1186/s40478-025-01974-5","DOIUrl":"10.1186/s40478-025-01974-5","url":null,"abstract":"<p><p>Acute ocular hypertension (AOH), a major cause of progressive irreversible vision loss, showed significant retinal ganglion cell (RGC) degeneration as well as selective RGC vulnerability upon functional tests, yet the underlyding mechanisms remain incompletely understood. Here, we report the activation of transient receptor potential ankyrin 1 (TRPA1), a mechanosensitive ion channel on RGCs under AOH by RT-qPCR, Western blot, immunofluorescent, flow cytometry and calcium imaging tests. Downstream CaMKII/CREB pathways were evaluated, showing significantly elevated phospho-CaMKII and down-regulated phospho-CREB1 under AOH. Further, by applying a modified whole-brain clearing method, the region-specific RGC axonal damage among lateral geniculate nuclei (LGN) subregions were adopted to detect the involvement of TRPA1 on selective RGC vulnerability. Together with tissue-specific knock-out or channel inhibition test, the exacerbation of TRPA1 on RGC degeneration as well as selective injury tendency under AOH was confirmed. In virtue of our modified whole-brain clearing method, our data confirmed the innovational method to study the mechanisms behind selective vulnerability of neuronal cells, and in the meantime revealed the potential therapeutic opportunity of targeting TRPA1 for patients suffering from AOH attack.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"70"},"PeriodicalIF":6.2,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787412","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":"IL13RA2-integrated genetically engineered mouse model allows for CAR T cells targeting pediatric high-grade gliomas.","authors":"M Seblani, M Zannikou, J T Duffy, T Joshi, R N Levine, A Thakur, M Puigdelloses-Vallcorba, C M Horbinski, J Miska, D Hambardzumyan, O J Becher, Irina V Balyasnikova","doi":"10.1186/s40478-025-01991-4","DOIUrl":"10.1186/s40478-025-01991-4","url":null,"abstract":"<p><p>Pediatric high-grade gliomas (pHGG) and pediatric diffuse midline gliomas (pDMG) are devastating diseases without durable and curative options. Although targeted immunotherapy has shown promise, the field lacks immunocompetent animal models to study these processes in detail. To achieve this, we developed a fully immunocompetent, genetically engineered mouse model (GEMM) for pDMG and pHGG that incorporates the glioma-associated antigen, interleukin 13 receptor alpha 2 (IL13RA2). Utilizing the RCAS-Tva delivery system in Nestin-Tva mice, we induced gliomagenesis by overexpressing PDGFB and deleting p53 (p53^fl/fl) or both p53 and PTEN (p53^fl/fl PTEN^fl/fl), with or without IL13RA2 in neonatal mice. De novo tumors developed in models with and without IL13RA2, showing no statistical difference in onset (n = 33, 38 days, p = 0.62). The p53^fl/fl PTEN^fl/fl tumors displayed more aggressive characteristics (n = 12, 31 days). Tumors exhibited features typical of high-grade glioma, including infiltration, pseudopalisading necrosis, and microvascular proliferation. They also showed a high Ki-67 index, variable IL13RA2 expression, a high frequency of CD11b + macrophages, and a low proportion of CD3 + T cells. The model proved effective for evaluating IL13RA2-targeted immunotherapies, with a significant response to CAR T-cell treatment that extended survival (46 days vs. 28 days control; p < 0.0001) and achieved 25% long-term survival in mice. This model facilitates the preclinical assessment of IL13RA2-directed therapies and holds potential for clinical application.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"69"},"PeriodicalIF":6.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770934","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":"PARP inhibition preserves cone photoreceptors in rd2 retina.","authors":"Pakize Nur Akkaya, María Miranda, Inmaculada Almansa, Cigdem Elmas, Dragana Trifunovic, Zohreh Hosseinzadeh, Ayse Sahaboglu","doi":"10.1186/s40478-025-01982-5","DOIUrl":"10.1186/s40478-025-01982-5","url":null,"abstract":"<p><p>The rd2 mouse model, characterized by a mutation in the Prph2 gene, exhibits abnormal development of photoreceptor outer segments, resulting in progressive retinal degeneration. While the correlation between poly-ADP-ribose polymerase (PARP) activity and the degeneration of rod photoreceptors is established in the rd2 model, the specific mechanism driving cone degeneration in this model remains unclear. Furthermore, it is yet to be determined whether inhibiting PARP activity can effectively impede the degeneration of cone photoreceptors in this context. We demonstrated that PARP inhibitors Olaparib, BMN-673, and 3-aminobenzamide (3AB), effectively reduced photoreceptor cell loss in the rd2 retina. Notably, rd2 retinas exhibited decreased cone density, but treatment with PARP inhibitors significantly protected cone photoreceptors. The PARP inhibitors, particularly BMN-673, demonstrated a significant protective effect as evidenced by increased rhodopsin expression within the outer segment and a concurrent decrease in Müller cell activity indicated by GFAP expression. The treatment also resulted in significant changes for markers of oxidative stress, such as glutathione (GSH), and oxidized glutathione (GSSG). Notably, the administration of PARP inhibitors also reduced CD9 expression (extracellular vesicle marker), which were significantly increased within the outer nuclear layer (ONL) in the rd2 retinas. Among PARP inhibitors, BMN-673 demonstrated the highest efficacy in preserving photoreceptors, particularly benefiting cone cells.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"68"},"PeriodicalIF":6.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762613","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":"C9ORF72 poly-PR disrupts expression of ALS/FTD-implicated STMN2 through SRSF7.","authors":"Karen S Wang, Julie Smeyers, Kevin Eggan, Bogdan Budnik, Daniel A Mordes","doi":"10.1186/s40478-025-01977-2","DOIUrl":"10.1186/s40478-025-01977-2","url":null,"abstract":"<p><p>A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and combined ALS/FTD. The repeat is transcribed in the sense and the antisense directions to produce several dipeptide repeat proteins (DPRs) that have toxic gain-of-function effects; however, the mechanisms by which DPRs lead to neural dysfunction remain unresolved. Here, we observed that poly-proline-arginine (poly-PR) was sufficient to inhibit axonal regeneration of human induced pluripotent stem cell (iPSC)-derived neurons. Global phospho-proteomics revealed that poly-PR selectively perturbs nuclear RNA binding proteins (RBPs). In neurons, we found that depletion of one of these RBPs, SRSF7 (serine/arginine-rich splicing factor 7), resulted in decreased abundance of STMN2 (stathmin-2), though not TDP-43. STMN2 supports axon maintenance and repair and has been recently implicated in the pathogenesis of ALS/FTD. We observed that depletion of SRSF7 impaired axonal regeneration, a phenotype that could be rescued by exogenous STMN2. We propose that antisense repeat-encoded poly-PR perturbs RBPs, particularly SRSF7, resulting in reduced STMN2 and axonal repair defects in neurons. Hence, we provide a potential link between DPRs gain-of-function effects and STMN2 loss-of-function phenotypes in neurodegeneration.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"67"},"PeriodicalIF":6.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717660","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}