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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg school of medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

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Dissecting the cell microenvironment of ovarian endometrioma through single-cell RNA sequencing

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Science China Life Sciences 2025年第1期 116-129页

作者： Jiangpeng Wu Siyu Xia Wenting Ye Yan Sun Jing Cai Fubing Yu Haiping Wen Xiuwei Yi Taikang Li Mingwei Chen Jiayun Chen Ge Song Chuanbin Yang Yali Song Jigang Wang Department of reproductive medicine Dongguan Maternal and Child Health Care Hospital Department of Urology and Shenzhen Clinical Research Centre for GeriatricsShenzhen People's HospitalSouthern University of Science and Technology State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical Sciences reproductive medicine Center Foshan Women and Children Hospital State Key Laboratory of Antiviral Drugs School of PharmacyHenan University

Ovarian endometrioma（OE）, also known as “chocolate cysts,” is a cystic mass that develops in the ovaries due to endometriosis and is a common gynecological condition characterized by the growth of endometrial tissue outside the uterus, leading to symptoms such as dysmenorrhea, pelvic pain, and infertility. However, the precise molecular and cellular mechanisms driving this pathophysiology remain largely unknown, posing challenges for diagnosis and treatment. Here, we employed integrated single-cell transcriptomic profiling of over 52,000 individual cells from endometrial tissues of OE patients and healthy donors and identified twelve major cell populations. We identified notable alterations in cell type-specific proportions and molecular signatures associated with OE. Notably, the activation of IGFBP5+macrophages with pro-inflammatory properties, NK cell exhaustion, and aberrant proliferation of IQCG+and KLF2+epithelium are key features and may be the potential mechanisms underlying the pathogenesis of OE. Collectively, our data contribute to a better understanding of OE at the single cell level and may pave the way for the development of novel therapeutic strategies.

关键词： ovary high-throughput sequencing transcriptomics gene expression analysis ligand-receptor analysis

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Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Regeneration Research 2025年第1期20卷 224-233页

作者： Yi Zhang Zhongwu Liu Michael Chopp Michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA Department of Pathology Henry Ford HospitalDetroitMIUSA Division of Pharmacology Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurological *** with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological *** vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke

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Establishment of human cerebral organoid systems to model early neural development and assess the central neurotoxicity of environmental toxins

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Neural Regeneration Research 2025年第1期20卷 242-252页

作者： Daiyu Hu Yuanqing Cao Chenglin Cai Guangming Wang Min Zhou Luying Peng Yantao Fan Qiong Lai Zhengliang Gao Fundamental Research Center Shanghai Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center)School of MedicineTongji UniversityShanghaiChina Institute of Geriatrics(Shanghai University) Affiliated Nantong Hospital of Shanghai University(The Sixth People’s Hospital of Nantong)Shanghai University School of MedicineNantongJiangsu ProvinceChina Shanghai Engineering Research Center of Organ Repair Shanghai University School of MedicineShanghaiChina Key Laboratory of Arrhythmias Ministry of EducationShanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina

Human brain development is a complex process,and animal models often have significant *** address this,researchers have developed pluripotent stem cell-derived three-dimensional structures,known as brain-like organoids,to more accurately model early human brain development and *** enable more consistent and intuitive reproduction of early brain development,in this study,we incorporated forebrain organoid culture technology into the traditional unguided method of brain organoid *** involved embedding organoids in matrigel for only 7 days during the rapid expansion phase of the neural epithelium and then removing them from the matrigel for further cultivation,resulting in a new type of human brain organoid *** cerebral organoid system replicated the temporospatial characteristics of early human brain development,including neuroepithelium derivation,neural progenitor cell production and maintenance,neuron differentiation and migration,and cortical layer patterning and formation,providing more consistent and reproducible organoids for developmental modeling and toxicology *** a proof of concept,we applied the heavy metal cadmium to this newly improved organoid system to test whether it could be used to evaluate the neurotoxicity of environmental *** organoids exposed to cadmium for 7 or 14 days manifested severe damage and abnormalities in their neurodevelopmental patterns,including bursts of cortical cell death and premature *** exposure caused progressive depletion of neural progenitor cells and loss of organoid integrity,accompanied by compensatory cell proliferation at ectopic *** convenience,flexibility,and controllability of this newly developed organoid platform make it a powerful and affordable alternative to animal models for use in neurodevelopmental,neurological,and neurotoxicological studies.

关键词： cadmium cell death cell proliferation cortical development environmental toxins neural progenitor cells neurogenesis neurotoxicology organoids stem cells

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Quality assurance and quality control in the laboratory andrology

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Asian Journal of Andrology 2010年第1期12卷 21-25页

作者： Allan A. Pacey school of medicine and Biomedical Sciences Academic Unit of Reproductive and Developmental Medicine the Universityof Shejfield the Jessop Wing Tree Root Walk Sheffield S102SF UK

Quality assurance （QA） and quality control （QC） are fundamental aspects of any laboratory measurement. However, in comparison with other medical disciplines, the need for QA and QC in laboratory andrology has been recognized only recently. Furthermore, there is evidence that the effort required to undertake QA and QC has not been wholly welcomed by some clinicians. Nevertheless, accrediting bodies and regulatory authorities increasingly require evidence that laboratories have effective QA and QC measures in place because both are central to the quality management processes. Following the publication of the 5th edition of the World Health Organization Laboratory Manual, existing QA and QC systems will need to be updated to take into account some of the methodological changes recommended by the manual. Three of these are discussed in this commentary; they relate to：（i） the move to infer semen volume from its weight; （ii） the re-classification of sperm motility grades from four to three; and （iii） the publication of a lower reference limit for morphology of 4% （with a corresponding 95% confidence interval of 3%-4%）. The importance of QA and QC in all laboratory tests, including up and coming new tests to assess sperm DNA integrity, is discussed. The need for adequate initial training and continuing professional development programmes to support laboratory scientists performing andrology is also described.

关键词： andrology health care quality assurance quality control semen analysis

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Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression

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Journal of Molecular Cell Biology 2020年第7期12卷 515-529页

作者： Yue Liu Chujun Zhang Shiyao Wang Yanqin Hu Jia Jing Luyao Ye Ran Jing Zhide Ding Department of Histology EmbryologyGenetics and Developmental BiologyShanghai Key Laboratory for Reproductive MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Clinical medicine Shanghai Jiao Tong University School of MedicineShanghai 200025China

After leaving the testis,mammalian sperm undergo a sequential maturation process in the epididymis followed by capacitation during their movement through the female reproductive *** phenotypic changes are associated with modification of protein phosphorylation and membrane remodeling,which is requisite for sperm to acquire forward motility and induce ***,the molecular mechanisms underlying sperm maturation and capacitation are still not fully ***,we show that PPP3R2,a testis-specific regulatory subunit of protein phosphatase 3(an isoform of calcineurin in the testis),is essential for sperm maturation and *** of Ppp3r2 in mice leads to male sterility due to sperm motility impairment and morphological *** very noteworthy change includes increases in sperm membrane ***,PPP3R2 regulates sperm maturation and capacitation via(i)modulation of membrane diffusion barrier function at the annulus and(ii)facilitation of cholesterol efflux during sperm *** together,PPP3R2 plays a critical role in modulating cholesterol efflux and mediating the dynamic control of membrane remodeling during sperm maturation and capacitation.

关键词： cholesterol metabolism Ppp3r2 sperm deformity sperm motility sperm maturation

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LGR4: A new receptor for a stronger bone

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Science China(Life Sciences) 2016年第7期59卷 735-736页

作者： Yunyun Jin Yingzi Yang Department of developmental Biology Harvard School of Dental Medicine

Bone formation and remodeling involves production of bone matrix by osteoblasts and its resorption by osteoclasts. Increased osteoclast activity or reduced osteoblast function leads to osteopenic disorders （Kong et al., 1999）. Therefore, it is crucial to understand mechanisms underlying osteoclast regulation. Such understanding will shed light on identify- ing potential therapeutic targets of osteoporosis, a disease caused by too much bone resorption or insufficient bone formation. RANKL-RANK signaling is required for osteo- clast, activating a variety of downstream signaling path- ways. RANK, also known as tumor necrosis factor （TNF） superfamily member 11 （TNFSF11）, has long been consid- ered to be the sole receptor for RANKL, also known as TNFRSFllA. （Hanada et al.. 2011）. In a recent study.

关键词：受体骨质疏松症肿瘤坏死因子破骨细胞成骨细胞信号路径细胞功能细胞活性

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Mutational analysis of the GATA4 gene in Chinese men with nonobstructive azoospermia

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Asian Journal of Andrology 2021年第2期23卷 205-210页

作者： Xu Zhang Tai-Jian Zhang Wen Liu Yun-Na Ning Yue-Hong Bian Yong-Zhi Cao Hong-Bin Liu Jin-Long Ma Hao-Bo Zhang Center for reproductive medicine Cheeloo College of MedicineShandong UniversityJinan 250012China National Research Centre for Assisted reproductive Technology and reproductive Genetics Shandong UniversityJinan 250012China Shandong Provincial Key Laboratory of Animal Cells and developmental Biology School of Life SciencesShandong UniversityQingdao 266237China

As a crucial transcription factor for spermatogenesis,GATA-binding protein 4(GATA4)plays important roles in the functioning of Sertoli and Leydig *** knockout of GATA4 in mice results in age-dependent testicular atrophy and loss of ***,whether GATA4 is associated with human azoospermia has not been ***,we analyzed the GATA4 gene by direct sequencing of samples obtained from 184 Chinese men with idiopathic nonobstructive azoospermia(NOA).We identified a missense mutation(c.191G>A,p.G64E),nine single-nucleotide polymorphisms(SNPs),and one rare variant(c.^(*)84C>T)in the 3′untranslated region(UTR).Functional studies demonstrated that the p.G64E mutation did not affect transactivation ability of GATA4 for spermatogenesis-related genes(claudin-11 and steroidogenic acute regulatory protein,Star),and the 3′UTR rare variant c.^(*)84C>T did not generate microRNA-binding sites to repress GATA4 *** our knowledge,this is the first report to investigate the association between GATA4 and azoospermia;our results indicate that mutations in GATA4 may not be pathogenic for NOA in Chinese men.

关键词： biological function GATA-binding protein 4(GATA4)mutation nonobstructive azoospermia

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Effects of aqueous leaf extract of Tridax procumbens on contractile activity of corpus cavernosum in N-nitro-L-arginine methyl ester-induced hypertensive male rats

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Journal of Integrative medicine 2018年第1期16卷 51-56页

作者： Shakiru Ademola Salami Hussein Mofomosara Salahdeen Evangelshane Chukwudubem Ugbebor Babatunde Adekunle Murtala Yinusa Raji Department of Physiology Lagos State University College of Medicine Laboratory for reproductive Physiology and developmental Programming Department of Physiology University of Ibadan

Objective： This study investigated the effects of aqueous leaf extract of Tridax procumbens （ALETP） on con- tractile activity of corpus cavernosum in N-nitro-L-arginine methyl ester （L-NAME）-induced hypertensive male rats. Methods： Twenty normal, adult male rats （130-150 g） were divided into four groups of five rats each. Group I （control） was given normal saline （0.6 mL/kg） and group II was given L-NAME （40 mg/kg） for 6 weeks. Groups Ill and IV also received L-NAME （40 mg/kg） for 6 weeks but were further co-treated with 100 and 200 mg/kg of ALETP, respectively, from week 4 to week 6. All treatments were given orally. Strips of corpus cavernosum from each of the four groups were exposed to increasing concentrations of acetyl~ choline （ACh） and sodium nitroprusside （SNP）（10^-9-10^-5 tool/L） after contraction with phenylephrine （10^-7 mol/L） to test for a dose-response effect, Response to potassium and calcium was also measured after cumulatively adding potassium and calcium （10-50 mmol/L） to potassium- and calcium-free organ chamber. Isometric contractions were recorded through an Ugo Basile data capsule acquisition system. Results： Mean arterial blood pressure was significantly reduced in the ALETP co-treated group compared to the control and L-NAME-only groups （P 〈 0.05）. Cavernosa strips from ALETP co-treated rats exhibited significant inhibition of contraction in response to phenylephrine, potassium chloride, and calcium chlo- ride （P 〈 0.05）. Relaxation in response to Ach and SNP was also significantly impaired in cavernosa strips from the L-NAME-only treated group （P 〈 0.05）, while ALETP co-treated groups showed enhanced per- centage relaxation. Conclusion： ALETP treatment of L-NAME-induced hypertensive rats promotes a relaxant effect on isolated cavernosa strips. ALETP shows potential in correcting erectile dysfunction in hypertension.

关键词： N-Nitro-L-arginine methyl ester Hypertensive Tridax procumbens Corpus cavernosum Relaxation Sodium nitroprusside Acetylcholine

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The second polar body contributes to the fate asymmetry in the mouse embryo

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National Science Review 2022年第7期9卷 32-42页

作者： Hongbin Jin Yang Han Huasong Wang J.Xiao He Li Weimin Shen Lin Zhang Luxi Chen Shunji Jia Ping Yuan Hui Chen Anming Meng Laboratory of Molecular developmental Biology State Key Laboratory of Membrane BiologyTsinghua-Peking Center for Life Sciences School of Life SciencesTsinghua University Center for reproductive Genetics and reproductive medicine Sun Yat-sen Memorial HospitalSun Yat-sen University Guangzhou Laboratory

The polar bodies(PBs) are extruded microcells during oocyte meiosis and generally regarded as inessentials for embryonic ***,PBs have been widelyused as important materials for pre-implantation genetic diagnosis in *** we report that the second PB(PB2) in the mouse zygote may play roles in cell-fate specification and post-implantation development.A subset of mRNAs encoding pluripotency-related factors are enriched in *** proteins maybe synthesized in PB2 after fertilization and transport from PB2 to the zygote before the two-cell *** PB2-attached blastomere(pbB) at the two-cell stage,compared to the other blastomere(npbB),likely contributes more descendants to the inner cell mass(ICM) lineage in the *** of PB2 from the zygote or transient blockage of material exchange between PB2 and the zygote by nocodazole treatment appears to cause a loss of the ICM fate bias of ***2 removal or nocodazole treatment also results in abnormal post-implantation *** of PB2 lysate into pbB of PB2-removed two-cell-stage embryos may reset the cell-fate preference and rescue post-implantation *** data collectively suggest that PB2 would demarcate the earliest cell-fate asymmetry of the mouse zygote and be required for post-implantation development.

关键词： mouse embryo polar body cell fate asymmetry

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