Neurobiology of Disease最新文献

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Pathological α-synuclein perturbs nuclear integrity 病理性α-synuclein干扰细胞核完整性。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-14 DOI: 10.1016/j.nbd.2025.107028
Michael Millett , Allison Comite , Elisabeth Martin Castosa , Anika Heuberger , Preston Wagner , Ignacio Gallardo , Jessica Reinhardt , Nicole Chambers , Dominic Hall , Evan Miller , Douglas Nabert , Barbara Balsamo , Stefan Prokop , Mark Moehle
{"title":"Pathological α-synuclein perturbs nuclear integrity","authors":"Michael Millett ,&nbsp;Allison Comite ,&nbsp;Elisabeth Martin Castosa ,&nbsp;Anika Heuberger ,&nbsp;Preston Wagner ,&nbsp;Ignacio Gallardo ,&nbsp;Jessica Reinhardt ,&nbsp;Nicole Chambers ,&nbsp;Dominic Hall ,&nbsp;Evan Miller ,&nbsp;Douglas Nabert ,&nbsp;Barbara Balsamo ,&nbsp;Stefan Prokop ,&nbsp;Mark Moehle","doi":"10.1016/j.nbd.2025.107028","DOIUrl":"10.1016/j.nbd.2025.107028","url":null,"abstract":"<div><div>Pathological aggregates of α-synuclein are a hallmark of a group of neurodegenerative disorders collectively termed synucleinopathies. The physiological function of α-synuclein, and the detrimental effects of the pathological variants of α-synuclein have been widely debated, but recent evidence has suggested an emerging consensus on a critical role for α-synuclein in regulating synaptic function. However, a controversial role for α-synuclein in nuclear function in both normal and pathogenic states has been proposed, and the degree to which α-synuclein localizes within the nucleus and subsequent impact on the nucleus are poorly understood. To begin to address this controversy, we employed synucleinopathy murine and cell culture models, as well as postmortem human Lewy Body Dementia tissue to elucidate the extent to which pathological α-synuclein localizes within the nuclear compartments, and the downstream consequences of this localization. We observed pathological aggregation of α-synuclein within the nucleus in both murine models and human postmortem Lewy Body Dementia cortex via quantitative super resolution microscopy. In both mouse and human brain tissue the presence of α-synuclein in the nucleus correlated with abnormal morphology of nuclei. This pathological accumulation of α-synuclein in the nucleus was not observed in control mice, human tissue without pathology, or control cells. We subsequently examined the correlated changes in nuclear function with pathological accumulation of α-synuclein in the nucleus. Synucleinopathy models displayed increased levels of the DNA damage marker 53BP1. Furthermore, cells with pathological α-synuclein exhibited elevated markers of nuclear envelope damage and abnormal expression of nuclear envelope repair markers. Our cell culture data also suggests altered RNA localization in response to pathological α-synuclein accumulation within the nucleus. Lastly, we show that nuclear Lewy-like pathology leads to increased sensitivity to nuclear targeted toxins. Taken together, these results rigorously illustrate nuclear localization of pathological α-synuclein with super resolution methodology and provide novel insight into the ensuing impact on nuclear integrity and function.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"214 ","pages":"Article 107028"},"PeriodicalIF":5.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cell-to-cell transmission of IAPP aggregates in T2DM induces neuronal death by triggering oxidative stress and ferroptosis T2DM中IAPP聚集体的细胞间传递通过触发氧化应激和铁下垂诱导神经元死亡。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-14 DOI: 10.1016/j.nbd.2025.107015
Honglin Zheng , Yapei Yuan , Na Zhang , Hang Zhang , Suying Duan , Chenyang Liu , Yaochong Zhang , Qiang Li , Han Liu , Mibo Tang , Haiyang Luo , Yuming Xu
{"title":"Cell-to-cell transmission of IAPP aggregates in T2DM induces neuronal death by triggering oxidative stress and ferroptosis","authors":"Honglin Zheng ,&nbsp;Yapei Yuan ,&nbsp;Na Zhang ,&nbsp;Hang Zhang ,&nbsp;Suying Duan ,&nbsp;Chenyang Liu ,&nbsp;Yaochong Zhang ,&nbsp;Qiang Li ,&nbsp;Han Liu ,&nbsp;Mibo Tang ,&nbsp;Haiyang Luo ,&nbsp;Yuming Xu","doi":"10.1016/j.nbd.2025.107015","DOIUrl":"10.1016/j.nbd.2025.107015","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) is associated with an elevated risk of neurodegenerative diseases, yet the underlying mechanisms remain elusive. A hallmark feature of T2DM is the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas, which may contribute to both pancreatic dysfunction and systemic pathological processes. In this study, we aimed to explore the role of IAPP aggregates as a possible mechanistic link in diabetes-associated neurodegeneration. Using co-culture systems with fluorescently labeled IAPP fibrils, we observed IAPP aggregates transfer between neurons via tunneling nanotubes (TNTs). RNA-seq analysis demonstrated that exposure to IAPP amyloid fibrils triggered substantial alterations in transcriptional profiles, enriching pathways related to oxidative phosphorylation and reactive oxygen species (ROS) production. Mechanistic investigations further showed that IAPP fibrils led to increased ROS levels, mitochondrial dysfunction, and ultimately neuronal death through ferroptosis. Specially, IAPP fibrils disrupted the p62-Keap1 interaction, blocking NRF2 nuclear translocation and altering the expression of ferroptosis-related proteins. Overall, these findings highlight the role of IAPP aggregates in T2DM associated with neurodegeneration, providing new insights into potential therapeutic targets for the relationship between these diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"214 ","pages":"Article 107015"},"PeriodicalIF":5.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Hearing the call of mitochondria: Insight into its role in sensorineural hearing loss 听到线粒体的呼唤:洞察其在感音神经性听力损失中的作用。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-11 DOI: 10.1016/j.nbd.2025.107030
Haojia He , Zhuoxue Han , Shuai Cheng , You Zhou
{"title":"Hearing the call of mitochondria: Insight into its role in sensorineural hearing loss","authors":"Haojia He ,&nbsp;Zhuoxue Han ,&nbsp;Shuai Cheng ,&nbsp;You Zhou","doi":"10.1016/j.nbd.2025.107030","DOIUrl":"10.1016/j.nbd.2025.107030","url":null,"abstract":"<div><div>Sensorineural hearing loss (SNHL) is a prevalent and complex auditory disorder with a multifactorial pathogenesis, in which mitochondrial dysfunction plays a pivotal role. Mitochondria are abundantly localized in critical structures of the inner ear, where they not only provide the substantial energy required for auditory transduction but also regulate key cellular processes. Growing evidence suggests that mitochondrial impairment, characterized by excessive reactive oxygen species (ROS) generation, dysregulated inflammatory responses, disrupted apoptosis, and mitochondrial DNA (mtDNA) mutations, is closely linked to the onset and progression of SNHL. Recent advances in mitochondria-targeted therapeutic strategies, such as antioxidant delivery, promotion of mitochondrial biogenesis, and mitochondrial gene therapy, have shown promising preclinical results. However, significant challenges remain in translating these approaches into clinical practice, particularly in terms of targeted delivery, long-term efficacy, and potential side effects. This comprehensive review systematically examines the molecular mechanisms underlying mitochondrial involvement in SNHL pathogenesis, evaluates recent progress in mitochondria-targeted interventions, and discusses current limitations and future directions in this rapidly evolving field. By integrating current knowledge and identifying key research gaps, this review aims to provide a solid theoretical foundation and fresh perspectives for the development of effective therapeutic strategies for SNHL.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107030"},"PeriodicalIF":5.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Atp7a deficiency induces axonal and myelin developmental defects in zebrafish via ferroptosis Atp7a缺乏通过铁下垂诱导斑马鱼轴突和髓鞘发育缺陷。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-11 DOI: 10.1016/j.nbd.2025.107027
You Wu , Jiahuan Li , Wenya Zhai , Wenye Liu , Hao Wu , Hong Liu , Junxia Min , Fudi Wang , Jing-Xia Liu
{"title":"Atp7a deficiency induces axonal and myelin developmental defects in zebrafish via ferroptosis","authors":"You Wu ,&nbsp;Jiahuan Li ,&nbsp;Wenya Zhai ,&nbsp;Wenye Liu ,&nbsp;Hao Wu ,&nbsp;Hong Liu ,&nbsp;Junxia Min ,&nbsp;Fudi Wang ,&nbsp;Jing-Xia Liu","doi":"10.1016/j.nbd.2025.107027","DOIUrl":"10.1016/j.nbd.2025.107027","url":null,"abstract":"<div><div><em>ATP7A</em> genetic mutations lead to Menkes disease (MD), a hereditary neurodegenerative disorder develops significant metabolic abnormalities including copper deficiency and hypomyelination, and even death before 3 years old. However, the underlying mechanisms remain poorly understood. In this study, a dysfunction in axons as evidenced by the shortened axons, reduced branching in each axon, thinner spinal myelin sheaths, and a significant decrease in neuronal membrane potential, was manifested in the central nervous system (CNS) of <em>atp7a</em><sup><em>−/−</em></sup> larvae. Atp7a is indispensable for the axonal survival in a cell-autonomous manner by fine-tuning copper homeostasis. The transcriptomics analysis identified a significant enrichment of ferroptosis among the differentially expressed genes (DEGs). Iron overload, GPX4 degradation, and lipid peroxidation, the fundamental characteristics of ferroptosis, were evident during <em>atp7a</em> ablation. More importantly, administration of ferroptosis inhibitor Fer-1 or iron chelator DFO, substantially suppressed ferroptosis and largely ameliorated axonal and myelin defects in <em>atp7a</em><sup><em>−/−</em></sup> larvae. Whereas, larvae exposed to ferroptosis inducer RSL3, and engineered larvae developing ferroptosis, phenocopied the myelin and axonal extension defects observed in <em>atp7a</em><sup><em>−/−</em></sup> mutants. Taken together, this study highlights the critical importance of <em>atp7a</em> in supporting axonal and myelin development during zebrafish embryogenesis by tightly restraining ferroptosis. This study will shed some light on the theoretical basis and therapeutic targets underlying ATP7A dysfunction induced neurodegenerative diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107027"},"PeriodicalIF":5.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment 24-羟基胆固醇水平升高可抵消冈田酸诱导的tau过度磷酸化和神经元形态损伤。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-11 DOI: 10.1016/j.nbd.2025.107029
Serena Giannelli , Francesca Eroli , Raúl Loera-Valencia , Valerio Leoni , Maria Latorre-Leal , Gabriella Testa , Erica Staurenghi , Barbara Sottero , Paola Gamba , Silvia Maioli , Gabriella Leonarduzzi
{"title":"Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment","authors":"Serena Giannelli ,&nbsp;Francesca Eroli ,&nbsp;Raúl Loera-Valencia ,&nbsp;Valerio Leoni ,&nbsp;Maria Latorre-Leal ,&nbsp;Gabriella Testa ,&nbsp;Erica Staurenghi ,&nbsp;Barbara Sottero ,&nbsp;Paola Gamba ,&nbsp;Silvia Maioli ,&nbsp;Gabriella Leonarduzzi","doi":"10.1016/j.nbd.2025.107029","DOIUrl":"10.1016/j.nbd.2025.107029","url":null,"abstract":"<div><div>Multiple findings underline a link between altered brain cholesterol metabolism and Alzheimer's disease (AD) pathogenesis. Physiologically, excess brain cholesterol is mainly converted into 24-hydroxycholesterol (24-OHC) by the neuron-specific enzyme CYP46A1. Of note, we previously observed in autopsy specimens from human AD brains that 24-OHC and, in parallel, <em>CYP46A1</em> expression decrease at advanced stages, suggesting a possible cause-effect between these reductions and AD progression. In the present study, we aimed to investigate whether maintaining high levels of 24-OHC, by its exogenous administration or <em>CYP46A1</em> overexpression, can counteract tau hyperphosphorylation and accumulation of prefibrillar tau oligomers. To create an AD-like <em>in vitro</em> model exhibiting tauopathy, we utilized okadaic acid (OKA), a chemical compound that induces tau hyperphosphorylation. Our data show that in 24-OHC-treated primary neurons derived from wild type mice and in neurons from <em>CYP46A1</em> overexpressing mice (CYP46Tg) elevated oxysterol levels effectively prevented tau hyperphosphorylation and oligomerization. Furthermore, the dendritic arborization decrease induced by OKA was prevented, maintaining the organization and stability of the neuronal cytoskeleton. While hypothesized underlying molecular mechanisms (GSK3β, CDK5, ERK1/2, and PP2A) seem not to be involved, the protective effect of 24-OHC remains evident. The data highlight the positive effects of 24-OHC and the need to prevent its reduction in the brain. This can be achieved either through the exogenous administration of 24-OHC using suitable technologies or by maintaining elevated levels and the activity of the enzyme CYP46A1. These therapeutic approaches could be useful to prevent or slow AD progression.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"214 ","pages":"Article 107029"},"PeriodicalIF":5.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The mediation effects of white matter microstructural abnormalities on the associations between cerebral small vessel disease burden and cognitive impairment 脑白质微结构异常在脑血管疾病负担与认知障碍关系中的中介作用。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-09 DOI: 10.1016/j.nbd.2025.107025
Chaofan Sui , Changhu Liang , Yian Gao , Na Wang , Xinyue Zhang , Yuanyuan Wang , Nan Zhang , Yena Che , Mengmeng Feng , Haotian Xin , Jing Li , Lingfei Guo , Hongwei Wen
{"title":"The mediation effects of white matter microstructural abnormalities on the associations between cerebral small vessel disease burden and cognitive impairment","authors":"Chaofan Sui ,&nbsp;Changhu Liang ,&nbsp;Yian Gao ,&nbsp;Na Wang ,&nbsp;Xinyue Zhang ,&nbsp;Yuanyuan Wang ,&nbsp;Nan Zhang ,&nbsp;Yena Che ,&nbsp;Mengmeng Feng ,&nbsp;Haotian Xin ,&nbsp;Jing Li ,&nbsp;Lingfei Guo ,&nbsp;Hongwei Wen","doi":"10.1016/j.nbd.2025.107025","DOIUrl":"10.1016/j.nbd.2025.107025","url":null,"abstract":"<div><h3>Background</h3><div>White matter (WM) microstructural deterioration is associated with a higher total cerebral small vessel disease (CSVD) burden, as assessed by magnetic resonance imaging (MRI) markers, and with more pronounced cognitive decline in CSVD patients. However, the relationships among CSVD burden, cognitive impairment and WM changes remain unclear. We aimed to characterize WM microstructural abnormalities in patients with different CSVD burdens and investigate the mechanism linking different CSVD burdens to cognitive decline.</div></div><div><h3>Methods</h3><div>This study included 56 patients with severe CSVD burden (CSVD-s), 109 patients with mild CSVD burden (CSVD-m) and 81 healthy controls. We used diffusion tensor imaging (DTI) and tract-based spatial statistics to detect WM diffusion changes between groups and then explored the relationships between different CSVD burdens, WM diffusion changes and cognitive function, especially to quantitatively analyze the possible mediating effect of WM microstructural alterations on CSVD burden and cognitive function.</div></div><div><h3>Results</h3><div>The CSVD-s group presented significantly decreased FA and increased AD, RD and MD in the forceps minor, bilateral anterior thalamic radiation (ATR), superior longitudinal fasciculus (SLF), corticospinal tract (CST) and inferior fronto-occipital fasciculus (IFOF). The simple mediation model revealed that the mean MD value of forceps minor and right IFOF, the mean FA value of the left CST and right IFOF, and the mean RD value of the left CST, SLF and right IFOF partially mediated the correlations between the CSVD burden and multiple cognitive scores.</div></div><div><h3>Conclusions</h3><div>Our findings offer potential neuroimaging targets for intervening in and improving cognitive dysfunction in patients with different CSVD burdens.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"214 ","pages":"Article 107025"},"PeriodicalIF":5.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Glucosylsphingosine is a potential fluid-based biomarker of lysosomal dysfunction in Cln3Δex7/8 mice 葡萄糖糖苷是Cln3Δex7/8小鼠溶酶体功能障碍的潜在液体生物标志物。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-08 DOI: 10.1016/j.nbd.2025.107026
Hallie Wald , Stephanie Cicalese , Lihang Yao , Nathan Hatcher , Weiwei Luo , Xiaolan Shen , Xiaoli Ping , Brie Culp , Dan Metzger , Mark Ault , Christian Nunes , Mali Cosden , Sarah Jinn , Jason Uslaner , Sean Smith , Jacob Marcus , Robert Drolet
{"title":"Glucosylsphingosine is a potential fluid-based biomarker of lysosomal dysfunction in Cln3Δex7/8 mice","authors":"Hallie Wald ,&nbsp;Stephanie Cicalese ,&nbsp;Lihang Yao ,&nbsp;Nathan Hatcher ,&nbsp;Weiwei Luo ,&nbsp;Xiaolan Shen ,&nbsp;Xiaoli Ping ,&nbsp;Brie Culp ,&nbsp;Dan Metzger ,&nbsp;Mark Ault ,&nbsp;Christian Nunes ,&nbsp;Mali Cosden ,&nbsp;Sarah Jinn ,&nbsp;Jason Uslaner ,&nbsp;Sean Smith ,&nbsp;Jacob Marcus ,&nbsp;Robert Drolet","doi":"10.1016/j.nbd.2025.107026","DOIUrl":"10.1016/j.nbd.2025.107026","url":null,"abstract":"<div><div>CLN3 disease is a rare fatal juvenile neurodegenerative lysosomal storage disease. Challenges in tracking underlying disease biology have hindered the identification of effective therapeutic targets and the ability to execute clinical trials in this rare disease. While diagnostic biomarkers are readily available, biomarkers that reflect the underlying core lysosome dysfunction are lacking. In the present study, CLN3<sup>Δex7/8</sup> iPSC derived models were used to link hallmark cellular pathology and lysosomal parameters at the cellular level to potential novel biomarkers. A <em>Cln3</em><sup>Δ<em>ex7/8</em></sup> disease mouse model was used to link established clinical diagnostic biomarkers and hallmark cellular pathology to novel biomarkers in tissue and biofluid in-vivo. Non-invasive retinal imaging modalities were used to identify the established visual dysfunction in the <em>Cln3</em><sup>Δ<em>ex7/8</em></sup> disease mouse model. These techniques better characterize significant and progressive retinal layer degeneration, bipolar cell dysfunction, and autofluorescent aggregate deposition in <em>Cln3</em><sup>Δ<em>ex7/8</em></sup> mice. Retinal imaging biomarkers also coincided with an increase in ATP synthase subunit C, a hallmark disease pathology, in the retina and brain. Additionally, quantitative lipidomic analyses of brain, retina and plasma specimens from <em>Cln3</em><sup>Δ<em>ex7/8</em></sup> mice identified alterations in levels of lysosomally-regulated sphingolipid species including marked accumulation of the Gaucher Disease biomarker glucosylsphingosine 18:1 (GlcSph). Sphingolipid concentrations were measured in CLN3<sup>Δex7/8</sup> iPSC-derived neural progenitor cells and cortical neurons. CLN3<sup>Δex7/8</sup> iPSCs exhibited marked elevation of GlcSph which coincided with hallmark accumulation in ATP synthase subunit C levels as well as reduced cellular lysosomal content and enzymatic function. The in vivo and in vitro data link alterations in established non-invasive clinical retinal biomarkers, hallmark subunit c accumulation and defects in lysosomal health to the accumulation of GlcSph. Taken together, these findings hold promise for future development of GlcSph as a potential biomarker of lysosomal function in CLN3 disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"214 ","pages":"Article 107026"},"PeriodicalIF":5.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia 鞘磷脂酶活性降低与前颗粒蛋白缺乏和额颞叶痴呆相关。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-07 DOI: 10.1016/j.nbd.2025.107024
Nicholas R. Boyle , Stephanie N. Fox , Aniketh S. Tadepalli , Nicholas T. Seyfried , Thomas Kukar , Eliana M. Ramos , Alissa L. Nana , Salvatore Spina , Lea T. Grinberg , Bruce L. Miller , William W. Seeley , Andrew E. Arrant , Erik D. Roberson
{"title":"Reduction of sphingomyelinase activity associated with progranulin deficiency and frontotemporal dementia","authors":"Nicholas R. Boyle ,&nbsp;Stephanie N. Fox ,&nbsp;Aniketh S. Tadepalli ,&nbsp;Nicholas T. Seyfried ,&nbsp;Thomas Kukar ,&nbsp;Eliana M. Ramos ,&nbsp;Alissa L. Nana ,&nbsp;Salvatore Spina ,&nbsp;Lea T. Grinberg ,&nbsp;Bruce L. Miller ,&nbsp;William W. Seeley ,&nbsp;Andrew E. Arrant ,&nbsp;Erik D. Roberson","doi":"10.1016/j.nbd.2025.107024","DOIUrl":"10.1016/j.nbd.2025.107024","url":null,"abstract":"<div><div>Loss-of-function mutations affecting the lysosomal protein progranulin are a leading cause of frontotemporal dementia. Progranulin mutations cause abnormalities in lysosomal lipid processing, particularly of sphingolipids, major components of neural cell membranes that play important signaling roles in the brain. Most work in this area has focused on two classes of sphingolipids, gangliosides and cerebrosides. Here, we examined enzymes involved in metabolism of another class of sphingolipids, the sphingomyelins, in both mouse models and patients with progranulin insufficiency. Acidic sphingomyelinase activity was decreased in progranulin knockout, but not heterozygous, mice. This resulted from post-transcriptional loss of acid sphingomyelinase (Smpd1) protein. Progranulin interacted with acid sphingomyelinase in immunoprecipitation and proximity ligation assays, suggesting a co-trafficking role like progranulin plays with other lysosomal enzymes. Consistent with that hypothesis, restoring progranulin in knockout mice using AAV-progranulin gene therapy corrected acid sphingomyelinase deficits. In post-mortem brain tissue from patients with frontotemporal dementia due to heterozygous progranulin mutations, neutral, but not acidic, sphingomyelinase activity was decreased. Neutral sphingomyelinase 2 (SMPD3), the predominant neutral sphingomyelinase in the brain, was reduced in patients with progranulin mutations. A similar trend (<em>p</em> = 0.0586) was seen in patients with sporadic frontotemporal lobar degeneration with type A TDP-43 pathology, but not in other types of frontotemporal lobar degeneration. The reduction of neutral sphingomyelinase 2 occurred in frontal, but not occipital cortex, correlating with the selective vulnerability of frontal regions seen in FTD. These data shed light on the role of progranulin in sphingomyelin metabolism and of this pathway in frontotemporal dementia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107024"},"PeriodicalIF":5.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nuclear localization of platelet activating factor receptor accounts for microglial phagocytosis in ischemic stroke 血小板活化因子受体的核定位是缺血性脑卒中小胶质细胞吞噬的原因。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-05 DOI: 10.1016/j.nbd.2025.107020
Xi-Yue Zhang , Hang Xu , Xue-Wei Ren , Qin-Xin Li , Chen Hong , Ye-Fan Chen , Jin Yang , Juan Ji , Ruo-Bing Guo , Xiu-Lan Sun
{"title":"Nuclear localization of platelet activating factor receptor accounts for microglial phagocytosis in ischemic stroke","authors":"Xi-Yue Zhang ,&nbsp;Hang Xu ,&nbsp;Xue-Wei Ren ,&nbsp;Qin-Xin Li ,&nbsp;Chen Hong ,&nbsp;Ye-Fan Chen ,&nbsp;Jin Yang ,&nbsp;Juan Ji ,&nbsp;Ruo-Bing Guo ,&nbsp;Xiu-Lan Sun","doi":"10.1016/j.nbd.2025.107020","DOIUrl":"10.1016/j.nbd.2025.107020","url":null,"abstract":"<div><div>Ischemic stroke (IS) is a leading cause of global morbidity and mortality. A critical strategy for improving the prognosis of IS involves mitigating neuronal loss to enhance neuroplasticity, with microglia playing a vital role in neuronal survival. The platelet activating factor receptor (PTAFR) participates in the pathological processes underlying IS; however, little is known about its mechanism in pathological stress. In this study, we investigated the potential role of PTAFR in regulating the microglia/macrophage phagocytosis of neurons, aiming to identify new therapeutic strategies for IS. The mRNA and protein expression levels of PTAFR were upregulated, peaking on day 5 post-ischemic stroke and gradually returning to baseline levels thereafter. PTAFR was found to mediate interactions between the microglia/macrophage and neurons in IS. Notably, the inhibition of phagocytosis of stressed-but-viable neurons following IS depends on the nuclear localization of PTAFR. Mechanistically, nuclear PTAFR recruited the transcription factor Specificity Protein 1 (SP1) to initiate the transcription of milk fat globule EGF factor 8 (MFGE8). In comparison to the membrane-impermeable antagonist Ginkgolide B, the membrane-permeable PTAFR antagonist Apafant significantly enhances neurological recovery in IS model mice. This effect is achieved by inhibiting PTAFR nuclear translocation, which reduces microglia/macrophage phagocytosis of stressed-but-viable neurons. Our findings provide insight into the mechanism of nuclear PTAFR-mediated microglia/macrophage phagocytosis and have significant implications for the selection of PTAFR antagonists in the treatment of ischemic stroke, particularly those targeting nuclear receptors.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107020"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway 抑制PTPRS功能不影响多巴胺能神经元的存活或再生,但会改变黑质纹状体通路的突触功能
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-07-05 DOI: 10.1016/j.nbd.2025.107023
Joshua Peter , Kaejaren C.N. Caldwell , Lucas McClain , Jason Tchieu , Ashley E. Ross , Yu Luo
{"title":"Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway","authors":"Joshua Peter ,&nbsp;Kaejaren C.N. Caldwell ,&nbsp;Lucas McClain ,&nbsp;Jason Tchieu ,&nbsp;Ashley E. Ross ,&nbsp;Yu Luo","doi":"10.1016/j.nbd.2025.107023","DOIUrl":"10.1016/j.nbd.2025.107023","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is characterized by midbrain dopaminergic (mDA) neuron degeneration in the ventral midbrain, contributing to debilitating motor symptoms. This study investigated whether Protein Tyrosine Phosphatase Receptor Sigma (PTPRS), a known inhibitor of axonal growth through chondroitin sulfate proteoglycan (CSPG) interaction, plays a role in mDA neuron survival, function, and regeneration in PD. Our data show that inhibition of PTPRS using intracellular sigma peptide (ISP) enhances human mDA neuron neurite outgrowth in vitro, suggesting an inhibitory role of this receptor in the differentiation of human embryonic stem cell (hESC)-derived mDA neurons in vitro. However, genetic deletion and pharmacological inhibition of PTPRS does not affect mDA neuron survival, axon density, or motor behavior in 6-OHDA unilateral partially lesioned mice. Similarly, mDA-specific deletion of <em>Ptprs</em> does not affect the basal behavioral measurement in cKO mice, including general locomotion and motor learning. Interestingly, however, <em>Ptprs</em> deletion led to a reduced response in the behavior sensitization to repeated methamphetamine (METH) exposure in cKO mice, suggesting a dampened response in synaptic function in cKO mice under these conditions. Ex vivo voltammetry recording in the striatum indeed shows altered parameters of dopamine (DA) release upon stimulation. These findings indicate that the inhibition of PTPRS function in human mDA neuron progenitors might be a promising strategy for enhancing neurite outgrowth or incorporation in host tissues in transplantation therapies. Finally, our data support that inhibition of PTPRS function in mDA neurons in adult mice in vivo could inhibit METH induced plasticity and behavioral sensitization.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107023"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144581284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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