Acta Neuropathologica Communications最新文献

{"title":"Neuropathology-based approach reveals novel Alzheimer's Disease genes and highlights female-specific pathways and causal links to disrupted lipid metabolism: insights into a vicious cycle.","authors":"Yin Jin, Apostolia Topaloudi, Sudhanshu Shekhar, Guangxin Chen, Alicia Nicole Scott, Bryce David Colon, Petros Drineas, Chris Rochet, Peristera Paschou","doi":"10.1186/s40478-024-01909-6","DOIUrl":"https://doi.org/10.1186/s40478-024-01909-6","url":null,"abstract":"<p><p>Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer's disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women's increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"1"},"PeriodicalIF":6.2,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926088","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}

{"title":"Decoding TDP-43: the molecular chameleon of neurodegenerative diseases.","authors":"Jixiang Zeng, Chunmei Luo, Yang Jiang, Tao Hu, Bixia Lin, Yuanfang Xie, Jiao Lan, Jifei Miao","doi":"10.1186/s40478-024-01914-9","DOIUrl":"10.1186/s40478-024-01914-9","url":null,"abstract":"<p><p>TAR DNA-binding protein 43 (TDP-43) has emerged as a critical player in neurodegenerative disorders, with its dysfunction implicated in a wide spectrum of diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer's disease (AD). This comprehensive review explores the multifaceted roles of TDP-43 in both physiological and pathological contexts. We delve into TDP-43's crucial functions in RNA metabolism, including splicing regulation, mRNA stability, and miRNA biogenesis. Particular emphasis is placed on recent discoveries regarding TDP-43's involvement in DNA interactions and chromatin dynamics, highlighting its broader impact on gene expression and genome stability. The review also examines the complex pathogenesis of TDP-43-related disorders, discussing the protein's propensity for aggregation, its effects on mitochondrial function, and its non-cell autonomous impacts on glial cells. We provide an in-depth analysis of TDP-43 pathology across various neurodegenerative conditions, from well-established associations in ALS and FTLD to emerging roles in diseases such as Huntington's disease and Niemann-Pick C disease. The potential of TDP-43 as a therapeutic target is explored, with a focus on recent developments in targeting cryptic exon inclusion and other TDP-43-mediated processes. This review synthesizes current knowledge on TDP-43 biology and pathology, offering insights into the protein's central role in neurodegeneration and highlighting promising avenues for future research and therapeutic interventions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"205"},"PeriodicalIF":6.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906175","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":"Tppp3 is a novel molecule for retinal ganglion cell identification and optic nerve regeneration.","authors":"Mishal Rao, Ziming Luo, Chia-Chun Liu, Chi-Yu Chen, Shining Wang, Michael Nahmou, Bogdan Tanasa, Aman Virmani, Leah Byrne, Jeffrey L Goldberg, José-Alain Sahel, Kun-Che Chang","doi":"10.1186/s40478-024-01917-6","DOIUrl":"10.1186/s40478-024-01917-6","url":null,"abstract":"<p><p>Mammalian central nervous system (CNS) axons cannot spontaneously regenerate after injury, creating an unmet need to identify molecular regulators to promote axon regeneration and reduce the lasting impact of CNS injuries. While tubulin polymerization promoting protein family member 3 (Tppp3) is known to promote axon outgrowth in amphibians, its role in mammalian axon regeneration remains unknown. Here we investigated Tppp3 in retinal ganglion cells (RGCs) neuroprotection and axonal regeneration using an optic nerve crush (ONC) model in the rodent. Single-cell RNA sequencing identified the expression of Tppp3 in RGCs of mice, macaques, and humans. Tppp3 overexpression enhanced neurite outgrowth in mouse primary RGCs in vitro, promoted axon regeneration, and improved RGC survival after ONC. Bulk RNA sequencing indicated that Tppp3 overexpression upregulates axon regeneration genes such as Bmp4 and neuroinflammatory pathways. Our findings advance regenerative medicine by developing a new therapeutic strategy for RGC neuroprotection and axon regeneration.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"204"},"PeriodicalIF":6.2,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902543","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":"A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (G₄C₂)₆₆ mouse model.","authors":"Emily G Thompson, Olivia Spead, Suleyman C Akerman, Carrie Curcio, Benjamin L Zaepfel, Erica R Kent, Thomas Philips, Balaji G Vijayakumar, Anna Zacco, Weibo Zhou, Guhan Nagappan, Jeffrey D Rothstein","doi":"10.1186/s40478-024-01911-y","DOIUrl":"10.1186/s40478-024-01911-y","url":null,"abstract":"<p><p>The G₄C₂ hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G₄C₂ hexanucleotide repeats. The model displays key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis. However, the AAV-(G₄C₂)₆₆ mouse model in this study has marginal neurodegeneration with negligible neuronal loss, or clinical deficits. Human C9orf72 is typically associated with altered TAR DNA-binding protein (TDP-43) function, yet studies of this rodent model revealed no significant evidence of TDP-43 dysfunction. While our findings indicate and support that this is a highly valuable robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G₄C₂) repeat driven DPR pathology, it is not suitable for investigating the development of disease- associated TDP-43 dysfunction or clinical impairment. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"203"},"PeriodicalIF":6.2,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891333","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":"3-Dimensional morphological characterization of neuroretinal microglia in Alzheimer's disease via machine learning.","authors":"Wissam B Nassrallah, Hao Ran Li, Lyden Irani, Printha Wijesinghe, Peter William Hogg, Lucy Hui, Jean Oh, Ian R Mackenzie, Veronica Hirsch-Reinshagen, Ging-Yuek Robin Hsiung, Wellington Pham, Sieun Lee, Joanne A Matsubara","doi":"10.1186/s40478-024-01898-6","DOIUrl":"10.1186/s40478-024-01898-6","url":null,"abstract":"<p><p>Alzheimer's Disease (AD) is a debilitating neurodegenerative disease that affects 47.5 million people worldwide. AD is characterised by the formation of plaques containing extracellular amyloid-β (Aβ) and neurofibrillary tangles composed of hyper-phosphorylated tau proteins (pTau). Aβ gradually accumulates in the brain up to 20 years before the clinical onset of dementia, making it a compelling candidate for early detection of AD. It has been shown that there is increased deposition of Aβs in AD patients' retinas. However, little is known about microglia's ability to function and clear Aβ within the retina of AD and control eyes. We labelled microglia with ionised calcium-binding adaptor molecule 1 (IBA-1) in AD and age-matched control donor retinas. We then used interactive machine learning to segment individual microglia in 3D. In the temporal mid-peripheral region, we found that the number of microglia was significantly lower in AD retinas compared to controls. Unexpectedly, the size of the microglia was significantly larger in the AD retinas compared to controls. We also labelled retinal microglia for Cluster of Differentiation 68 (CD68), a transmembrane glycoprotein expressed by cells in the monocyte lineage and a marker of phagocytic activity and activated microglia. The size of CD68 + cells was statistically different between AD and control microglial, with CD68 + cells being larger in AD. In contrast, there was no difference in either size or shape for CD68- microglia between the two groups, suggesting an important difference in the active states of CD68 + microglia in AD retina. There was also significantly increased CD68 immunoreactivity in individual microglia within the AD group. Overall, this study reveals unique differences in the size and activity of the retinal microglia, which may relate to their potential chronic activation due to increased levels of Aβs in the AD retina.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"202"},"PeriodicalIF":6.2,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885085","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":"JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain.","authors":"Xi-Biao He, Fang Guo, Wei Zhang, Jiacheng Fan, Weidong Le, Qi Chen, Yongjun Ma, Yong Zheng, Sang-Hun Lee, Hui-Jing Wang, Yi Wu, Qinming Zhou, Rui Yang","doi":"10.1186/s40478-024-01912-x","DOIUrl":"10.1186/s40478-024-01912-x","url":null,"abstract":"<p><p>Midbrain dopamine (mDA) neurons participate in a wide range of brain functions through an intricate regulation of DA biosynthesis. The epigenetic factors and mechanisms in this process are not well understood. Here we report that histone demethylase JMJD3 is a critical regulator for DA biosynthesis in adult mouse mDA neurons. Mice carrying Jmjd3 conditional knockout or undergoing pharmaceutical inhibition of JMJD3 showed consistent reduction of DA content in midbrain and striatum. Histological examination of both mice confirmed that TH and NURR1, two key molecules in DA biosynthesis pathway, were decreased in mDA neurons. Mechanistic experiments in vivo and in vitro further demonstrated that the transcriptions of Th and Nurr1 in mDA neurons were suppressed by JMJD3 deficiency, because of increased repressive H3K27me3 and attenuated bindings of JMJD3 and NURR1 on the promoters of both genes. On behavioral level, a significant prolonged inflammation-induced mechanical hyperalgesia was found in conditional knockout mice regardless of sex and age, whereas motor function appeared to be intact. Our findings establish a novel link between DA level in mDA neurons with intrinsic JMJD3 activity, and suggest prolonged chronic inflammatory pain as a major loss-of-function consequence.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"201"},"PeriodicalIF":6.2,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880976","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":"Adequate post-ischemic reperfusion of the mouse brain requires endothelial NFAT5.","authors":"Reiner Kunze, Paul Wacker, Paula Breuer, Emil Nasyrov, Ivan M Kur, Andreas Weigert, Andreas H Wagner, Hugo H Marti, Thomas Korff","doi":"10.1186/s40478-024-01918-5","DOIUrl":"10.1186/s40478-024-01918-5","url":null,"abstract":"<p><p>Severity and outcome of strokes following cerebral hypoperfusion are significantly influenced by stress responses of the blood vessels. In this context, brain endothelial cells (BEC) regulate inflammation, angiogenesis and the vascular resistance to rapidly restore perfusion. Despite the relevance of these responses for infarct volume and tissue recovery, their transcriptional control in BEC is not well characterized. We revealed that oxygen and nutrient-deprived BEC activate nuclear factor of activated T-cells 5 (NFAT5)-a transcription factor that adjusts the cellular transcriptome to cope with environmental stressors. We hypothesized that NFAT5 controls the expression of genes regulating the response of BEC in the ischemic brain. The functional relevance of NFAT5 was assessed in mice, allowing the conditional EC-specific knock-out of Nfat5 (Nfat5^(EC)-/-). Cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) followed reperfusion up to 28 days. While loss of endothelial Nfat5 did not evoke any phenotypic abnormalities in mice under control conditions, infarct volumes, neurological deficits and the degree of brain atrophy were significantly pronounced following MCAO as compared to control animals (Nfat5^fl/fl). In contrast, MCAO-induced edema formation, inflammatory processes and angiogenesis were not altered in Nfat5^(EC)-/- mice. RNAseq analyses of cultured BEC suggested that loss of NFAT5 impairs the expression of Kcnj2 encoding a potassium channel that may affect reperfusion. In fact, lower levels of KCNJ2 were detected in arterial endothelial cells of Nfat5^(EC)-/- versus Nfat5^fl/fl mice. Laser speckle contrast imaging of the brain revealed an impaired perfusion recovery in Nfat5^(EC)-/- versus Nfat5^fl/fl mice after MCAO.Collectively, NFAT5 in arterial BEC is required for an adequate reperfusion response after brain ischemia that is presumably dependent on the maintenance of Kcnj2 expression. Consequently, impairment of the protective role of endothelial NFAT5 results in enlarged infarct sizes and more severe functional deficits of brain functions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"200"},"PeriodicalIF":6.2,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11663326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875715","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":"Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis.","authors":"Gracious D S Kasheke, Basmah A M Hendy, Gabriel G Dorighello, Nonthué A Uccelli, Jean-David M Gothié, Robyn J Novorolsky, Madison J Oulton, Jude Asainayagam, Adam I Makarov, Kaitlyn S Fraser, Vidyasagar Vuligonda, Martin E Sanders, Timothy E Kennedy, George S Robertson","doi":"10.1186/s40478-024-01904-x","DOIUrl":"10.1186/s40478-024-01904-x","url":null,"abstract":"<p><p>Evidence that myelin repair is crucial for functional recovery in multiple sclerosis (MS) led to the identification of bexarotene (BXT). This clinically promising remyelinating agent activates multiple nuclear hormone receptor subtypes implicated in myelin repair. However, BXT produces unacceptable hyperlipidemia. In contrast, IRX4204 selectively activates the retinoid X receptor (RXR). Given compelling links between RXR activation and increased myelin repair, we employed IRX4204 to investigate the impact of RXR agonism alone on functional recovery in mice subjected to experimental autoimmune encephalomyelitis (EAE). Since gait deficits are common in MS, we used machine learning to obtain highly sensitive and reliable measurements of sagittal hindleg joint movements for mice walking on a treadmill. IRX4204 not only blocked the progressive loss of knee and ankle movements but also reversed joint movement impairments in EAE mice. Our biochemical, transcriptional and histological measurements in spinal cord suggest these gait improvements reflect increased axon survival and remyelination and reduced inflammation. Using microglia, astrocytes and oligodendrocyte progenitor cells, we present additional data suggesting that IRX4204 may act on multiple glial subtypes to orchestrate myelin repair. These results inform the discovery of restorative neural therapeutics for MS by demonstrating that selective RXR agonism is sufficient for effective myelin repair. Moreover, our findings support the therapeutic potential of IRX4204 to promote functional recovery in MS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"197"},"PeriodicalIF":6.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870954","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":"BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson's disease.","authors":"Aya Jishi, Di Hu, Yutong Shang, Rihua Wang, Steven A Gunzler, Xin Qi","doi":"10.1186/s40478-024-01915-8","DOIUrl":"10.1186/s40478-024-01915-8","url":null,"abstract":"<p><p>Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficiency leads to mitochondrial dysfunction, including reduced membrane potential and increased reactive oxygen species (ROS) production upon administration of a stressor, which in turn promotes αSyn oligomerization. Mechanistically, BCKDK interacts with the NDUFS1 subunit of Complex I to stabilize its function. Loss of BCKDK disrupts this interaction, leading to Complex I destabilization and enhanced αSyn aggregation. Notably, restoring BCKDK expression in neuron-like cells rescues mitochondrial integrity and restores Complex I activity. Similarly, in patient-derived iPS cells differentiated to form dopaminergic neurons, NDUFS1 and phosphorylated aSyn levels are partially restored upon BCKDK expression. These findings establish a mechanistic link between BCKDK deficiency, mitochondrial dysfunction, and αSyn pathology in PD, positioning BCKDK as a potential therapeutic target to mitigate mitochondrial impairment and neurodegeneration in PD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"198"},"PeriodicalIF":6.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870744","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":"CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS.","authors":"Olivia Keeley, Emma Mendoza, Druv Menon, Alyssa N Coyne","doi":"10.1186/s40478-024-01916-7","DOIUrl":"10.1186/s40478-024-01916-7","url":null,"abstract":"<p><p>Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent \"activation\" is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"199"},"PeriodicalIF":6.2,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870748","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}