American Journal of Pathology最新文献_第2页

The Substructure of the Endothelial Glycocalyx in Rat Aorta and Its Interaction with the Low-Density Lipoproteins. 大鼠主动脉内皮糖萼亚结构及其与低密度脂蛋白的相互作用。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-07-09 DOI: 10.1016/j.ajpath.2025.06.005

Hongyan Kang, Guiqin Yan, Xiaoqian Lin, Yuwen Tian, Jiaxin Yin, Jiao Liu, Zhilan Deng, Jiaxin Guo, Jinyan Lu, Xubo Lin, Li Wang, Anqiang Sun, Xiaoyan Deng, Guixue Wang, Yubo Fan

{"title":"The Substructure of the Endothelial Glycocalyx in Rat Aorta and Its Interaction with the Low-Density Lipoproteins.","authors":"Hongyan Kang, Guiqin Yan, Xiaoqian Lin, Yuwen Tian, Jiaxin Yin, Jiao Liu, Zhilan Deng, Jiaxin Guo, Jinyan Lu, Xubo Lin, Li Wang, Anqiang Sun, Xiaoyan Deng, Guixue Wang, Yubo Fan","doi":"10.1016/j.ajpath.2025.06.005","DOIUrl":"10.1016/j.ajpath.2025.06.005","url":null,"abstract":"The influx and retention of the low-density lipoproteins (LDLs) in the subendothelial space are one of the early events of atherosclerosis. Initially, LDLs must traverse the endothelial glycocalyx, which is increasingly recognized for its critical role in preventing LDL penetration. However, the precise substructure of the glycocalyx and its working mechanism are still unknown. Herein, a well-preserved porous mesh-like glycocalyx at the luminal surface of rat aortas, demonstrated by high-pressure freezing/freeze substitution transmission electron microscopy, shows three subtypes. Mathematical modeling suggests the dense lower glycocalyx (0.2 to 2.9 μm) shows similar arrangement to that reported in microvessels, with the partition coefficient of LDL equaling 0. The other sparse higher one (0.8 to 17.3 μm) contributes to mechanotransduction. LDL affinity column chromatography combined with proteomic analysis, colocalization analysis, and cell transport experiments verifies, for the first time, that the glycocalyx does bind LDLs both in vitro and in vivo, but does not retain LDLs. Two-photon laser scanning microscopic imaging of mouse ear arterioles suggests that the electrostatic repulsion between LDL and glycocalyx is dominant relative to binding. These findings reveal the arrangement of dense lower glycocalyx together with its electrostatic repulsion toward LDLs works in preventing LDL penetration.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615819","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

Characterizing Kupffer Cell Production of CD5 Antigen-Like and Its Function on Regulating Migration of Natural Killer T Cells. Kupffer细胞产生CD5L的特性及其在调节自然杀伤T细胞迁移中的作用

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-07-08 DOI: 10.1016/j.ajpath.2025.06.003

Handan Hong, Taojian Tu, Diala Alhousari, Lina He, Richa Aggarwal, Anketse Debebe, Chien-Yu Chen, Karam Ashouri, Anastasia Martynova, Christina Nakhoul, Ali Rastegarpour, Sina Baharlouei, Dai Peng, Eileen X Stile, Meisam Razaviyayn, Sze-Chuan Suen, Enrique Cadenas, Houda Alachkar, Weiming Yuan, Keigo Machida, Hidekazu Tsukamoto, Liyun Yuan, Anthony El-Khoueiry, Bangyan L Stiles

{"title":"Characterizing Kupffer Cell Production of CD5 Antigen-Like and Its Function on Regulating Migration of Natural Killer T Cells.","authors":"Handan Hong, Taojian Tu, Diala Alhousari, Lina He, Richa Aggarwal, Anketse Debebe, Chien-Yu Chen, Karam Ashouri, Anastasia Martynova, Christina Nakhoul, Ali Rastegarpour, Sina Baharlouei, Dai Peng, Eileen X Stile, Meisam Razaviyayn, Sze-Chuan Suen, Enrique Cadenas, Houda Alachkar, Weiming Yuan, Keigo Machida, Hidekazu Tsukamoto, Liyun Yuan, Anthony El-Khoueiry, Bangyan L Stiles","doi":"10.1016/j.ajpath.2025.06.003","DOIUrl":"10.1016/j.ajpath.2025.06.003","url":null,"abstract":"CD5 antigen-like (CD5L) is a multifunctional glycoprotein characterized for its role in the lipid metabolism, particularly within macrophages. In the liver, CD5L strongly correlates with liver injury. This study explored the role of CD5L on liver lipid accumulation and inflammatory response. We show that CD5L promotes lipid uptake in hepatocytes and stellate cells. In multiple models of liver injury, expression of Cd5l is associated with that of Clec4f, a marker for liver macrophages, consistent with its role as a macrophage survival factor. Using transwell assay, we also demonstrated a novel function of CD5L on promoting migration of natural killer T cells. This effect is independent of CD36, the characterized receptor of CD5L. This effect is also observed with liver macrophages, which are the cellular source for CD5L, and blocking CD5L attenuates natural killer T cell migration induced by liver macrophages. Finally, we showed that plasma levels of CD5L correlate with poor patient response to immune check point therapy that is dependent on response of T-cell populations. In addition, plasma CD5L levels correlate with levels of steatosis and severity of steatotic liver injury. Because liver steatosis is correlated with poor patient response to immune checkpoint therapy, these data suggest that plasma CD5L levels may be used to predict patient response to immune checkpoint therapy.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607161","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

Endothelial Cell Stimulator of Interferon Genes Regulates IL-6 Production and Is Required for Pathologic Cardiac Hypertrophy and Contractile Dysfunction in Experimental Heart Failure. 内皮细胞STING调节il - 6的产生，是实验性心力衰竭病理性心肌肥大和收缩功能障碍所必需的。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-07-08 DOI: 10.1016/j.ajpath.2025.06.004

Erin Sanders, Kuljeet Kaur, Noah Wagner, Ramona Emig, Mark Aronovitz, Abraham L Bayer, Brandon Theall, Albert Tai, Nina Martino, Miranda E Good, Alejandro P Adam, Robert Blanton, Pilar Alcaide

{"title":"Endothelial Cell Stimulator of Interferon Genes Regulates IL-6 Production and Is Required for Pathologic Cardiac Hypertrophy and Contractile Dysfunction in Experimental Heart Failure.","authors":"Erin Sanders, Kuljeet Kaur, Noah Wagner, Ramona Emig, Mark Aronovitz, Abraham L Bayer, Brandon Theall, Albert Tai, Nina Martino, Miranda E Good, Alejandro P Adam, Robert Blanton, Pilar Alcaide","doi":"10.1016/j.ajpath.2025.06.004","DOIUrl":"10.1016/j.ajpath.2025.06.004","url":null,"abstract":"Capillary rarefaction and cardiomyocyte (CM) hypertrophy are hallmarks of the complex syndrome of heart failure (HF), a leading cause of hospitalization and death. Molecular signals within and between cellular components of the heart have emerged as central hubs that modulate cardiac pathophysiology. Here, we discovered that the stimulator of interferon genes (STING) is highly expressed in human and mouse cardiac endothelial cells (ECs) and is activated in the onset of HF. Using global and inducible EC-specific STING-/- mice, we report that EC STING is required for contractile dysfunction in an experimental model of HF induced by transverse aortic constriction, through the regulation of CM hypertrophy and capillary rarefaction. We report that ECs sorted from transverse aortic constriction EC-STING-/- mice are enriched in gene sets related to integrin and cell adhesion to extracellular matrix compared with controls. CellChat analysis of human cardiac cells from patients with nonischemic cardiomyopathy revealed EC-CM communication, and mechanistically, we found that STING activation induces IL-6 secretion. Furthermore, EC-derived IL-6 is necessary to induce prohypertrophic gene expression in CMs in a STING-dependent manner. The study demonstrates a novel role for STING in ECs, contributing to hypertrophy and contractile dysfunction in experimental HF.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607162","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

Single-Cell Sequencing Has Revealed the Palmitoylation Landscape in Lung Adenocarcinoma and Identified ABHD17C as a Novel Biomarker. 单细胞测序揭示了肺腺癌中的棕榈酰化景观，并鉴定出ABHD17C是一种新的生物标志物。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-27 DOI: 10.1016/j.ajpath.2025.05.024

Benliang Wei, Anhong Li, Guofa Zhao, Rongfang Liu, Peng Liu, Xu Zhang, Fangchao Zhao, Shujun Li, Xinyue Zhang, Xuguang Zhang

{"title":"Single-Cell Sequencing Has Revealed the Palmitoylation Landscape in Lung Adenocarcinoma and Identified ABHD17C as a Novel Biomarker.","authors":"Benliang Wei, Anhong Li, Guofa Zhao, Rongfang Liu, Peng Liu, Xu Zhang, Fangchao Zhao, Shujun Li, Xinyue Zhang, Xuguang Zhang","doi":"10.1016/j.ajpath.2025.05.024","DOIUrl":"10.1016/j.ajpath.2025.05.024","url":null,"abstract":"Protein S-palmitoylation, a reversible posttranslational modification, is crucial for tumor progression. However, the palmitoylation landscape in tumor cells and its variability within different tumor cell populations remain underexplored. We analyzed protein palmitoylation using 23 palmitoyl-acyltransferases and 7 de-palmitoyl-acyltransferases. Through copy number variation, pseudotime, enrichment, and cell-cell communication analyses, we explored heterogeneity among epithelial cells in lung adenocarcinoma. Palmitoylation levels are elevated in normal epithelial cells, whereas depalmitoylation predominates in tumor-derived cells. As clinical stage advances, palmitoylation declines and depalmitoylation increases. We identified a C4 epithelial subtype associated with epithelial-to-mesenchymal transition and angiogenesis, marked by low palmitoylation and high depalmitoylation. This subtype, located at the end of the tumorigenic trajectory, shows intense communication with fibroblasts and endothelial cells but minimal interaction with immune cells, indicating enhanced invasiveness and immune evasion. ABHD17C, a key marker of the C4 subtype, was found to regulate tumor cell proliferation, and its knockdown reduced growth and increased apoptosis. We identified a C4 epithelial subtype linked to lung adenocarcinoma metastasis and highlighted ABHD17C as a potential biomarker and therapeutic target.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526082","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

DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa. 色素性视网膜炎小鼠模型的DNA甲基化动力学。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-24 DOI: 10.1016/j.ajpath.2025.05.021

Lu Huang, Lydia Tai Wai, Kin-Sang Cho, Ajay Ashok, Maximilian Braun, Menglu Yang, Karen Chang, Anton Lennikov, Sarita Pooranawattanakul, Farris Elzaridi, Hio Tong Kam, Yizhen Tang, Qingfeng Li, Dong Feng Chen

{"title":"DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa.","authors":"Lu Huang, Lydia Tai Wai, Kin-Sang Cho, Ajay Ashok, Maximilian Braun, Menglu Yang, Karen Chang, Anton Lennikov, Sarita Pooranawattanakul, Farris Elzaridi, Hio Tong Kam, Yizhen Tang, Qingfeng Li, Dong Feng Chen","doi":"10.1016/j.ajpath.2025.05.021","DOIUrl":"10.1016/j.ajpath.2025.05.021","url":null,"abstract":"Retinitis pigmentosa (RP) is a group of sight-threatening genetic diseases characterized by progressive degeneration of photoreceptors, leading to severe vision loss from childhood to adulthood. With limited treatment options, understanding the molecular mechanisms underlying RP is crucial. Evidence points to increased DNA methylation, especially in degenerating photoreceptors, as a contributing factor to retinal damage in RP. To exploit the molecular insights into methylation-driven pathways, this study investigates the DNA methylation patterns and their potential roles in photoreceptor degeneration in a mouse model of RP, specifically mice carrying a rhodopsin deficiency (Rho-/-). We observed elevated levels of DNA methyltransferases (DNMTs) and DNA methylation during photoreceptor degeneration. Importantly, weekly intravitreal injections of the pan DNMT inhibitor decitabine in Rho-/- mice significantly improved photoreceptor morphology and visual function, as evidenced by electroretinogram, spectral-domain optical coherence tomography, and optomotor response-based visual behavior assays. Further histologic and immunohistochemical assessments revealed increased survival of cone photoreceptors and thicker outer nuclear layers in decitabine-treated mice compared with controls. Together, these findings reveal that the dynamics of DNA methylation correlate with photoreceptor degeneration. Inhibition of DNMTs mitigated the morphologic and functional impairments associated with the genetic defects in photoreceptors, suggesting that targeting DNA methylation could be a viable therapeutic strategy for neuroprotection in RP.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504504","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

Activin A Prevents Hyperresponsiveness to Vascular Endothelial Growth Factor in Pathologic Blood Vessels by Perturbing the Trafficking of Activated Vascular Endothelial Growth Factor Receptor 2. 激活素A通过干扰活化的VEGFR2的运输来防止病理血管中对VEGF的高反应性。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-24 DOI: 10.1016/j.ajpath.2025.05.022

Basma Baccouche, Maximilian McCann, Janani Rajasekar, Nguyễn Thị Thanh Nhàn, Kaori Yamada, Andrius Kazlauskas

{"title":"Activin A Prevents Hyperresponsiveness to Vascular Endothelial Growth Factor in Pathologic Blood Vessels by Perturbing the Trafficking of Activated Vascular Endothelial Growth Factor Receptor 2.","authors":"Basma Baccouche, Maximilian McCann, Janani Rajasekar, Nguyễn Thị Thanh Nhàn, Kaori Yamada, Andrius Kazlauskas","doi":"10.1016/j.ajpath.2025.05.022","DOIUrl":"10.1016/j.ajpath.2025.05.022","url":null,"abstract":"Although quality-of-life compromising afflictions, such as diabetic retinopathy (DR), are driven by vascular endothelial growth factor (VEGF), there is a growing appreciation that the concentration of VEGF is not the only influencer of vascular dysfunction within the retina. Activin A (activin), a ligand of the transforming growth factor-β superfamily, attenuated VEGF-induced vascular endothelial-cadherin disorganization, pore formation, and permeability of primary human retinal endothelial cells. Efforts to further investigate the mechanism of this phenomenon revealed that activin reduced the expression of Rab11, which was required for the activin effect. The activin effect was not observed in cells with suppressed expression of the endosomally localized protein tyrosine phosphatase (PTP1b), whereas protein tyrosine phosphatases present on the plasma membrane were dispensable. Activin attenuated VEGF-mediated phosphorylation of VEGF receptor 2 at 30 minutes and longer post-stimulation time points. Together, these data support the concept that activin suppressed VEGF-induced barrier relaxation by perturbing trafficking of activated VEGF receptor 2. This activin-based suppression of responsiveness to VEGF was compromised in the endothelium of pathologic blood vessels from patients who developed end-stage proliferative DR. This defect rendered human retinal endothelial cell hyperresponsive to VEGF and was not observed in retinal vessels of diabetic mice, which do not develop the angiogenic forms of DR. These data provide novel insights regarding the pathogenesis of proliferative DR in patients.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504503","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

From Disruption of Muscle Membrane to Muscle Membrane Repair 从肌膜破坏到肌膜修复

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-23 DOI: 10.1016/j.ajpath.2024.09.013

Shin'ichi Takeda

引用次数: 0

IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis. 白细胞介素-6反式信号调控酒精相关性肝炎中性粒细胞炎症

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-23 DOI: 10.1016/j.ajpath.2025.05.023

Gaurav Sarode, Ming-Fo Hsu, Fawaz G Haj, Sergio Barace, Josepmaria Argemi, Mengfei Liu, Prisha Pandita, Sheng Cao, Vijay H Shah, Dorina Gui, Ramon Bataller, Vikrant Rachakonda

{"title":"IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis.","authors":"Gaurav Sarode, Ming-Fo Hsu, Fawaz G Haj, Sergio Barace, Josepmaria Argemi, Mengfei Liu, Prisha Pandita, Sheng Cao, Vijay H Shah, Dorina Gui, Ramon Bataller, Vikrant Rachakonda","doi":"10.1016/j.ajpath.2025.05.023","DOIUrl":"10.1016/j.ajpath.2025.05.023","url":null,"abstract":"Alcohol-associated hepatitis (AH) is a form of acute-on-chronic liver failure characterized by intrahepatic neutrophilic inflammation. In hepatocytes, IL-6 can signal through membrane-bound (classical signaling) or soluble (trans-signaling; TS) IL-6 receptors (IL-6Rs) to regulate liver injury responses. This study determined the role of IL-6TS in the pathophysiology of AH. Liver RNA sequencing in alcohol-related liver disease patients demonstrated declining IL-6R expression with increasing AH severity, and transforming growth factor (TGF)-β1 was the strongest negative regulator of IL-6R expression; however, STAT3-dependent gene expression was increased in severe AH. In vitro, HepG2 cells were exposed to TGF-β1 to inhibit IL-6R expression, followed by STAT3 activation with either IL-6 to stimulate classical signaling, or hyper-IL-6, a recombinant IL-6/IL-6R α peptide, to activate trans-signaling. Hyper-IL-6, but not IL-6, restored STAT3 activation in the face of suppressed IL-6R. RNA sequencing was performed on hyper-IL-6 stimulated cells, yielding a gene signature that identified a subset of AH patients with: i) enhanced IL-6TS activity, ii) increased intrahepatic neutrophilic infiltration, and iii) transcriptional enrichment of leukocyte migration pathways. Female mice treated with 10-day chronic-plus-binge ethanol exhibited enhanced STAT3 activation despite reduced hepatic IL-6R expression, leading to increased expression of neutrophilic activators, with colocalization of Ly6G+ leukocytes and STAT3+ hepatocytes. IL-6TS preserves hepatocyte STAT3-dependent gene expression and neutrophilic inflammation in AH.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493448","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

Retraction Notice to “Insulin-Induced Gene 2 Expression Is Associated with Breast Cancer Metastasis” [Am J Pathol 191 (2021) 385–395] “胰岛素诱导的基因2表达与乳腺癌转移相关”的撤回通知[J] .中华病理学杂志，1999,19 (2):385-395]

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-23 DOI: 10.1016/j.ajpath.2025.04.012

Ning Lu , Mei Zhang , Lu Lu , Yan-zhao Liu , Xiao-dong Liu , Hai-hong Zhang

引用次数: 0

Novel Kinesin Family 1A Variants Linked to Atypical Parkinsonism Elicit Altered Neuronal TDP-43 Interactions and Dendritic Atrophy. 与非典型帕金森病相关的新型运动蛋白家族1A变异可引起神经元TDP-43相互作用改变和树突状萎缩。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2025-06-19 DOI: 10.1016/j.ajpath.2025.05.018

Houman Homayoun, Michael R DeChellis-Marks, Julia Kofler, Gabriella Fricklas, Amanda M Gleixner, Fang-Cheng Yeh, David Lacomis, Charleen T Chu, Christopher J Donnelly

{"title":"Novel Kinesin Family 1A Variants Linked to Atypical Parkinsonism Elicit Altered Neuronal TDP-43 Interactions and Dendritic Atrophy.","authors":"Houman Homayoun, Michael R DeChellis-Marks, Julia Kofler, Gabriella Fricklas, Amanda M Gleixner, Fang-Cheng Yeh, David Lacomis, Charleen T Chu, Christopher J Donnelly","doi":"10.1016/j.ajpath.2025.05.018","DOIUrl":"10.1016/j.ajpath.2025.05.018","url":null,"abstract":"Analysis of induced pluripotent stem cell (iPSC)-derived neurons from the son of a father-son pair with novel familial variants of uncertain significance in kinesin family 1A (KIF1A) [c.408C>G (p.Asp136Glu); c.3914G>A (p.Arg1305His)] reveal pathologic features of altered TDP-43 localization, interactions, and stunted dendritic arbors. Both patients developed spasticity and parkinsonism in their mid-60s, with the father dying at age 71 years. There was impaired putamenal dopamine uptake with preserved uptake in the caudate nuclei, and decreased anisotropy by tractography in multiple motor pathways. Given shared transcriptional mechanisms of hindbrain and spinal cord developmental patterning among neurons of the motor circuitry, iPSC-derived motor neurons from fibroblasts donated by the son were generated to investigate the impact of KIF1A mutations on TDP-43 subcellular localization, biochemical interactions of endogenous wild type and mutant KIF1A and endogenous TDP-43, and the pathologic impact of these KIF1A variants on dendritic arborization using Sholl analysis. Neuropathologic assessment of the father, who shared the same KIF1A variants, revealed tauopathy and TDP-43 proteinopathy throughout the brainstem. Quantitative imaging of patient iPSC neurons identified TDP-43 mislocalization to the soma and dendritic atrophy. The KIF1A variant also elicited decreased biochemical interactions of both itself and TDP-43 with a spectrum of known TDP-43-associated proteins. These data suggest that this novel KIF1A mutant mediates altered TDP-43 interactions, stunting of the synaptic architecture, and clinical phenotypes coincident with neurodegenerative movement disorders.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339819","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