更新于：2024-11-01

Paraparesis, Spastic

痉挛性截瘫

更新于：2024-11-01

基本信息

别名

Lower Extremity Weakness, Spastic、PARAPARESIS SPASTIC、Parapareses, Spastic

+ [16]

简介

Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.

关联

项与痉挛性截瘫相关的药物

ASO-005-02

靶点

TECPR2

作用机制

TECPR2调节剂

在研机构

Q-State Biosciences, Inc.

原研机构

Q-State Biosciences, Inc.

在研适应症

痉挛性截瘫

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与痉挛性截瘫相关的临床试验

NCT05544175 / Not yet recruitingN/AIIT

NEUROMOdulation Pain Therapy in Combination With Intensive Physiotherapy on a Neurophysiological Basis Improves Not Only Pain But Also Mobility in Spastic Paraparesis

In this project, the aim is to verify that neuromodulation therapy (spinal cord stimulation) in combination with intensive physiotherapy on a neurophysiological basis will lead to the restoration of mobility of lower limbs.

开始日期2024-10-01

申办/合作机构

University of Charles

NCT06330311 / Active, not recruitingN/AIIT

Effectiveness of Whole-Body Vibration on Lower Limb Motor Function and Spasticity in Children With Spastic Cerebral Palsy

Cerebral Palsy is the most common cause of severe physical disability in childhood and may present difficulties and limitations that will have an impact on their independence and integration in all social areas.
Within interventions aiming to manage CP Whole-Body Vibration (WBV) has shown some benefits such as reducing spasticity or improving strength and functionality of the lower limbs.
The aim of this study is to assess the effectiveness on motor function and spasticity of the lower limbs by adding an intervention with WBV to an evidence-based multimodal physiotherapy treatment in children with CP.

开始日期2024-03-29

申办/合作机构

Universidad Complutense de Madrid

NCT06059872 / RecruitingN/AIIT

What Makes a Responder, a Responder? Biomarkers to Help Identify Responders and Resistors to High-intensity Interval Training for Lower Extremity Chronic Stroke

Stroke survivors with lower limb disability can improve their walking speed with high-intensity interval training (HIIT) rehabilitation therapy. However, some individuals may not respond to HIIT even when fully adherent to the program. To address this, the investigators propose to build a predictive model that identifies if a Veteran with chronic subcortical stroke will improve their walking speed with HIIT by incorporating blood lactate as an early predictor of exercise response, and inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and regional cerebral blood flow (CBF) as predictors of the brain's potential to respond, while also taking into consideration other factors such as comorbidities, demographics, and fitness levels.

开始日期2024-01-01

申办/合作机构

VA Office of Research and Development

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100 项与痉挛性截瘫相关的临床结果

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100 项与痉挛性截瘫相关的转化医学

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0 项与痉挛性截瘫相关的专利（医药）

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1,675

项与痉挛性截瘫相关的文献（医药）

2024-11-01·Spine

The Need for a Standardized Approach

Review

作者: Iyer, Rajiv R. ; Findlay, Matthew C. ; Kelly, Michael P. ; Ravindra, Vijay M. ; Johansen, Chase M. ; Kestle, John R.W. ; Brockmeyer, Douglas L. ; Tenhoeve, Samuel A. ; Newton, Peter O. ; Gonda, David D.

Study Design.Systematic review.Objective.To identify commonly reported indications and outcomes in spinal column shortening (SCS) procedures.Background.SCS is a surgical procedure used in patients with tethered cord syndrome—characterized by abnormal attachment of neural components to surrounding tissues—to shorten the vertebral column, release tension on the spinal cord/neural elements, and alleviate associated symptoms.Patients and Methods.PubMed and EMBASE searches captured SCS literature published between 1950 and 2023. Prospective/retrospective cohort studies and case series were included without age limit or required follow-up period. Review articles without new patient presentations, meta-analyses, systematic reviews, conference abstracts, and letters were excluded. Studies included adult and pediatric patients.Results.The 29 identified studies represented 278 patients (aged 5–76 yr). In 24.1% of studies, patients underwent primary tethered cord syndrome intervention through SCS. In 41.4% of studies, patients underwent SCS after failed previous primary detethering (24.1% of studies were mixed and 10.3% were unspecified). The most commonly reported nongenitourinary/bowel surgical indications were back pain (55.2%), lower-extremity pain (48.3%), lower-extremity weakness (48.3%), lower-extremity numbness (34.5%), and lower-extremity motor dysfunction (34.5%). Genitourinary/bowel symptoms were most often described as nonspecific bladder dysfunction (58.6%), bladder incontinence (34.5%), and bowel dysfunction (31.0%). After SCS, nongenitourinary/bowel outcomes included lower-extremity pain (44.8%), back pain (31.0%), and lower-extremity sensory and motor function (both 31.0%). Bladder dysfunction (79.3%), bowel dysfunction (34.5%), and bladder incontinence (13.8%) were commonly reported genitourinary/bowel outcomes. In total, 40 presenting surgical indication categories and 33 unique outcome measures were reported across studies. Seventeen of the 278 patients (6.1%) experienced a complication.Conclusion.The SCS surgical literature displays variability in operative indications and postoperative outcomes. The lack of common reporting mechanisms impedes higher-level analysis. A standardized outcomes measurement tool, encompassing both patient-reported outcome measures and objective metrics, is necessary.Level of Evidence.Level IV.

2024-11-01·Human Genetics

Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis

Article

作者: Freihuber, Cécile ; Durr, Alexandra ; Courtin, Thomas ; Mignot, Cyril ; Guillaud-Bataille, Marine ; Lallemant, Pauline ; Guillot-Noel, Lena ; Stevanin, Giovanni ; de Sainte Agathe, Jean-Madeleine ; Issa, Mahmoud ; Gleeson, Joseph G ; Zaki, Maha S ; Isapof, Arnaud ; Renaldo, Florence ; Cogan, Guillaume ; Gleeson, Joseph G. ; Keren, Boris ; Zaki, Maha S. ; Buratti, Julien ; Howarth, Robyn

Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement.

2024-10-01·Journal of Neurosurgery: Pediatrics

Predictors of postsurgical retethering in pediatric fatty or tight filum terminale: a systematic review and meta-analysis of 1167 patients

Article

作者: Guirguis, Mina ; Bhalla, Shubhang ; Wang, Jason ; Whittemore, Brett ; Farid, Michael ; Barrie, Umaru ; Smith, Parker D. ; Darko, Kwadwo

OBJECTIVEThe objective of this study was to characterize pediatric patients with tight filum terminale (TFT) or fatty filum terminale (FFT) who experienced retethering after transection of the filum, and to determine the risk factors for retethering.METHODSA systematic review was conducted on May 31, 2023, using PubMed, Google Scholar, SCOPUS, and Web of Science databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies detailing retethering following transection for TFT or FFT. Studies were then screened using the Newcastle-Ottawa Scale for risk of bias assessment.RESULTSEleven articles met the inclusion criteria with an overall cohort of 1167 patients evaluated for retethering following transection for TFT or FFT. The combined retethering rate across all retrospective studies was 3.4% (95% CI 1.6%–5.2%). A random-effects model was used to estimate the prevalence of presenting symptoms, with the most common being lower-extremity weakness in the overall cohort (54.5%, 95% CI 32.6%–76.4%) and bowel or bladder dysfunction in the retethered cohort (57.9%, 95% CI 41.1%–74.8%). Patients who experienced retethering had a similar estimated prevalence of low-lying conus (71.1%, 95% CI 45.1%–97.1%) compared with the overall cohort (51.1%, 95% CI 39.3%–63.0%). The most common complication following surgery for the overall cohort was a wound complication (2.7%, 95% CI 0.8%–4.6%). Postoperative CSF leakage (OR 13.8, 95% CI 3.9–49.4) was a strong predictor of retethering. Sensory changes at initial presentation were also found to be a predictor of retethering (OR 2.9, 95% CI 1.3–6.5). Low-lying conus was not predictive of retethering.CONCLUSIONSPreoperative sensory changes and postsurgical CSF leakage were associated with an increased retethering rate following transection of the filum in cases of tethered cord syndrome secondary to fatty filum terminale.

项与痉挛性截瘫相关的新闻（医药）

2024-07-08

·派真生物PackGene

一周要闻丨基因治疗要闻速递第110期

行业动态速览热点聚焦 01 只有一个患者的临床试验！AAV基因治疗对抗无药可治的超罕见绝症痉挛性截瘫50型（spastic paraplegia type 50，SPG50）是一种超罕见的疾病，全球患儿数量只有约80人，而在加拿大仅有迈克尔一人被报道患有SPG50。SPG50患者会经历发育迟缓、言语功能障碍以及进行性的四肢瘫痪，通常活不到成年阶段。在2022年，迈克尔参与了以AAV为基础的SPG50基因疗法临床试验，同时他也是这项试验唯一的患者。这项1期临床试验的结果已经以“AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient”为题，发表在《自然-医学》上，结果支持了基因疗法拯救迈克尔计划的初步成功。推荐阅读：只有一个患者的临床试验！对抗无药可治的超罕见绝症，7岁的他迎来治愈曙光 02 利用mRNA瞬时构建TCR-T细胞，治疗晚期难治性高MSI结直肠癌患者！结直肠癌（CRC）是全球第三大常见癌症，尽管局部性 CRC 生存率高，但转移性CRC的5年生存率仅约为11%。近期，挪威奥斯陆大学医学院研究团队报道了在患有 LS 和晚期转移性 MSI-H CRC 的患者中，首次使用 mRNA 电穿孔进行瞬时表达 Radium-1 TCR 在临床患者中应用，相关文章以简报形式，发表在Cell ASGCT系列杂志《Molecular Therapy》上。推荐阅读：利用mRNA瞬时构建TCR-T细胞，治疗晚期难治性高MSI结直肠癌患者！ 03超70%患者达主要终点！潜在“first-in-class"CAR-T疗法积极临床结果公布近日，Cartesian Therapeutics宣布了其在研mRNA细胞疗法Descartes-08在全身性重症肌无力（MG）患者中的2b期临床试验的积极顶线结果。推荐阅读：超70%患者达主要终点！潜在“first-in-class"CAR-T疗法积极临床结果公布 04 CDE公开征求意见！规范腺相关病毒载体基因治疗产品非临床研究近日，中国国家药品监督管理局（NMPA）药品审评中心（CDE）发布了《腺相关病毒载体基因治疗产品非临床研究技术指导原则（征求意见稿）》，旨在规范并促进腺相关病毒（AAV）载体基因治疗产品的非临床研究，为该类产品的临床试验和上市提供科学依据。推荐阅读：CDE公开征求意见！规范腺相关病毒载体基因治疗产品非临床研究创新突破 01 AAV递送工程，最新Science！美国怀特海德生物医学研究所Jonathan S. Weissman和MIT/哈佛大学Sonia M. Vallabh等人开发了一种名为CHARM的紧凑表观基因组编辑器，单个AAV就能实现对其的有效递送。在小鼠实验中，CHARM可以敲低全脑中80%以上的朊病毒基因，同时不会改变潜在的DNA序列。该编辑器可以在沉默靶标后实现自我沉默，从而限制长期表达的潜在不利影响。CHARM代表了一种治疗模式，可应用于由有害蛋白质的毒性积聚引起的一系列其他疾病。因此，CHARM最终可能对人类产生类似于碱基编辑、先导编辑等工具的巨大影响。推荐阅读：AAV递送工程，最新Science！ 02 减毒病毒疗法助力癌症治疗！近日，一篇发表在国际杂志Journal of Clinical Investigation上题为“An attenuated lymphocytic choriomeningitis virus vector enhances tumor control in mice partly via IFN-I”的研究报告中，来自美国西北大学等机构的科学家们通过研究发现，一种减毒的淋巴细胞性脑膜脊髓炎病毒（LCMV）能够有效清除小鼠体内的肿瘤，并使幸存小鼠对后续肿瘤发展具备更强抵抗力。研究结果揭示了特殊LCMV载体的强大抗肿瘤效应，并揭示了其抗肿瘤疗效背后的多种分子机制，为癌症治疗提供了新思路。推荐阅读：减毒病毒疗法助力癌症治疗！ 03 苏州儿童医院团队鉴定新的神经母细胞瘤超级增强子近日，苏州大学附属儿童医院潘健和张子木团队在 Neuro-Oncology 上发表题为 Super-enhancer-driven IRF2BP2 enhances ALK activity and promotes neuroblastoma cell proliferation 的文章，鉴定出一个由NB主转录因子簇MYCN, MEIS2和HAND2 调节激活的新SE区域，导致靶基因IRF2BP2的异常高表达。IRF2BP2能够与该NB主转录因子簇之间形成正反馈回路，从而在NB中建立稳定持续的高水平IRF2BP2的表达。此外，IRF2BP2还能够与先驱因子AP-1家族成员通过调节NB易感基因ALK的染色质可及性，维持NB细胞增殖与存活。这项研究为NB生物学提供了新的见解，并有可能为NB下调ALK提供替代策略。推荐阅读：苏州儿童医院团队鉴定新的神经母细胞瘤超级增强子资本速递 01 14.5亿欧元！GSK与mRNA巨头达成协议 7月4日，葛兰素史克(LSE/NYSE: GSK) 与 CureVac N.V. (Nasdaq: CVAC)宣布，两家公司已将现有合作重组为一项新的授权协议，使双方能优先投资及专注各自的mRNA开发活动。根据协议条款，CureVac将获得4亿欧元的预付款，以及至多10.5亿欧元的开发、监管和销售里程碑以及分层版税，累计近15亿欧元（117.68亿人民币，以最新汇率计算）的款项。根据新的协议条款，GSK将全面负责以上候选疫苗的开发和生产。GSK将拥有全球商业化候选疫苗的权利。推荐阅读：14.5亿欧元！GSK与mRNA巨头达成协议 02 1.7亿美元B轮融资！创新基因疗法注册性试验已启动近日，眼科基因治疗公司Beacon Therapeutics宣布已完成1.7亿美元的 B轮融资。该融资由Forbion领投，TCGX和Advent Life Sciences参与，现有投资者Syncona Limited、Oxford Science Enterprises、牛津大学也参与其中。这些资金将用以支持Beacon用于治疗X连锁视网膜色素变性（XLRP）的主打在研基因疗法AGTC-501的持续临床开发，并支持该公司的干性老年性黄斑变性（dAMD）项目的1/2期临床试验。推荐阅读：1.7亿美元B轮融资！创新基因疗法注册性试验已启动 03 Cartesian LNP-mRNA细胞疗法临床成功，新获融资1.3亿美金！近日，Cartesian Therapeutics宣布签订了一份证券购买协议，用于私人投资公开股权（“PIPE”）融资，预计将为公司带来大约1.30亿美元的总收益。推荐阅读：Cartesian LNP-mRNA细胞疗法临床成功，新获融资1.3亿美金！参考资料： 1.https://mp.weixin.qq.com/s/pbFanDicHXsfZAAXnHZW7Q 2.https://mp.weixin.qq.com/s/GkEznBO7lvdlTThW362Erg 3.https://mp.weixin.qq.com/s/b-q0nD0P1VgnX7wlv8URnA 4.https://finance.sina.com.cn/stock/med/2024-07-07/doc-incchkam5612250.shtml 5.https://mp.weixin.qq.com/s/TO5oI7Nw1cz1tu5WkVFgbw 6.https://mp.weixin.qq.com/s/1lMb-HSL-sia6Aho0qUKCw 7.https://mp.weixin.qq.com/s/7z3SMvOeAFlrZYfdXw3kPw 8.https://mp.weixin.qq.com/s/gT_omNuemkJLTux5e6Bhjw 9.https://mp.weixin.qq.com/s/sfYhDx1ZdkS4RWdPF_oiBw 10.https://mp.weixin.qq.com/s/T9swMSo3FHpn7wrWK1xHWg 关于派真生物

细胞疗法基因疗法信使RNA免疫疗法临床1期

2024-07-05

·药明康德

只有一个患者的临床试验！对抗无药可治的超罕见绝症，7岁的他迎来治愈曙光

▎药明康德内容团队编辑 “直到时间尽头，我们也要找到拯救儿子的方法。”皮罗沃拉基斯（Pirovolakis）夫妇面对医生时，言语无比坚定。他们的孩子迈克尔（Michael）于2017年来到人世，谁也没有料到这个普通又幸福的家庭后面即将会迎来狂风骤雨。大约在迈克尔5个月时，他的母亲察觉到孩子有点难以言说的不对劲，迈克尔在抬头或者举起手指时总是有气无力。在去往医院后，医生让迈克尔接受了肌张力的训练，之后迈克尔的症状有了一定的好转。但医生仍然表示出了他们的担忧，因为后续检测显示迈克尔的大脑白质和胼胝体有着明显异常。也是这个时刻，迈克尔的病情急转直下，训练带来的改善成果完全消失，并且他还产生了癫痫的症状。很明显这不是简单的肌张力问题，找到迈克尔真正的病因已经刻不容缓。 ▲迈克尔在加拿大多伦多病童医院（图片来源：参考资料[2]，credit：The Hospital For Sick Children） 2019年，分析结果显示迈克尔的AP4M1基因出现了突变，这直接导致了衔接蛋白复合体4的功能缺陷。这类基因缺陷疾病也被称作痉挛性截瘫50型（spastic paraplegia type 50，SPG50），患者会经历发育迟缓、言语功能障碍以及进行性的四肢瘫痪，通常活不到成年阶段。从患病率来说，SPG50是一种超罕见的疾病，全球患儿数量只有约80人，而在加拿大仅有迈克尔一人被报道患有SPG50，很明显现有疗法无法帮到迈克尔。为了拯救自己的孩子，皮罗沃拉基斯夫妇成立了一个“治愈SPG50”（CureSPG50）的基金会，为迈克尔募集到了大量治疗费用，同时加拿大多伦多病童医院（The Hospital for Sick Children，SickKids）的医生开始全力为迈克尔设计一种可行的治疗方案。 ▲从确诊到基因疗法开展期间的时间线（图片来源：参考资料[1]）幸运的是，SPG50并非没有逆转的可能。它的病因源头AP4M1基因长度并不长，只有1359个碱基对，这让基因疗法有了介入和发挥的可能性。借助腺相关病毒（AAV）载体，医生可以将正确的AP4M1基因输送进迈克尔体内，当AAV进入细胞后会在细胞核内转录和翻译携带的健康AP4M1基因，进而帮助恢复正常的AP4M1蛋白功能。在2022年，迈克尔参与了以AAV为基础的SPG50基因疗法临床试验，同时他也是这项试验唯一的患者。研究人员将携带正常AP4M1基因的AAV载体注射到了迈克尔的脑脊液中，这些AAV载体会迅速地前往神经细胞发挥作用。现在，这项1期临床试验的结果已经以“AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient”为题，发表在《自然-医学》上。根据论文，研究者注射的AAV达到了1×1015载体基因组（vg），也是目前通过脑脊液注射的最大病毒载量。由于迈克尔原本缺乏正确的AP4M1蛋白，为了避免突然大量出现的健康蛋白引起免疫反应，研究者还额外给其进行了AP4M1蛋白免疫抑制治疗。在治疗12个月后，迈克尔并没有展示出严重的不良反应，期间他经历过中性粒细胞减少症和腹痛症状，但都很快地恢复了过来，分析显示他的腹痛症状来自艰难梭菌感染和抗生素副作用。与此同时，各项评估数据显示迈克尔的各项疾病进展中止了，脑部和脊柱没有炎症变化，大脑萎缩没有进展。此外，迈克尔的疾病症状出现了改善的信号，在治疗前他的下肢痉挛较为严重，仅可以爬行和独自短暂在桌旁站立。 ▲基因疗法让迈克尔多个指标得到改善（图片来源：参考资料[1]）而在治疗期终点，迈克尔已经可以自己用脚后跟站立了，并且能站立更长时间，也可以使用辅助装置行走，这在治疗之前都是无法做到的。发育评估也显示，他的运动行为有所改善，迈克尔父母也近一年没有反馈过他发生跌倒、癫痫现象。这些结果都支持了基因疗法拯救迈克尔计划的初步成功。从确诊到使用上基因疗法，医生与研究人员只花费了约3年的时间，这也向我们证明了基因疗法存在快速研发、使用的可能性，这种速度对开展个体化治疗有重要意义。在迈克尔父母眼中，这只是征服SPG50的一个起点，他们的基金会仍然会继续执行下去，为后续临床试验做好准备，“这不仅仅只是拯救迈克尔，也是为未来更多SPG50患儿带去希望。” 参考资料： [1] Dowling, J.J., Pirovolakis, T., Devakandan, K. et al. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med (2024). https://doi.org/10.1038/s41591-024-03078-4 [2] Gene therapy halts progression of rare genetic condition in young boy. Retieved July 1, 2024 from https://www.eurekalert.org/news-releases/1049675 [3] Battling SPG50 and changing the world. Retrieved July 1, 2024 from https://www.jax.org/news-and-insights/2022/August/battling-spg50-and-changing-the-world# 本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

基因疗法临床结果临床1期

2024-03-28

·生物探索

Nature | 中国科学院王晓晨/冯巍发现溶酶体膜分裂因子HPO-27

引言溶酶体是降解和信号传导中心，对体内平衡、发育和衰老至关重要。为了满足不同的细胞需求，溶酶体通过不断的融合和分裂重塑其形态和功能。人们对裂变的分子基础所知甚少。2024年3月27日，中国科学院生物物理研究所王晓晨及冯巍共同通讯在Nature在线发表题为“The HEAT repeat protein HPO-27 is a lysosome fission factor”的研究论文，该研究证明，HEAT重复蛋白HPO-27是一种溶酶体裂变因子。HPO-27的缺失会损害溶酶体的裂变，导致过度的管状网络最终崩溃。HPO-27及其人类同源物MROH1被RAB-7募集到溶酶体中，并在裂解位点富集。超分辨率成像、阴性染色电镜和体外重构实验显示，HPO-27和MROH1分别在蠕虫和哺乳动物细胞中自组装介导溶酶体小管的收缩和断裂，并在体外组装切断支撑的膜管。HPO-27的缺失会影响溶酶体的形态、完整性和降解活性，从而影响动物的发育和寿命。因此，HPO-27和MROH1作为自组装分裂因子维持溶酶体稳态和功能。溶酶体是协调细胞代谢和清除的主要降解细胞器和信号中心。溶酶体功能障碍与代谢紊乱、神经退行性疾病和年龄相关病理有关，这突出了溶酶体在生理和衰老中的重要性。溶酶体经历不断的融合和裂变。它们与其他细胞器融合，获得必需的成分和酸度，接收用于降解的货物，并履行分泌功能。为了平衡这种向内的物质流动，溶酶体进行裂变以保持其稳态的数量、形状、大小、组成和功能，并完成再生。可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合物在被RAB-7和/或ARL8效应物拴住后以反式方式组装，以驱动溶酶体与货物递送囊泡融合，对溶酶体膜裂变所知甚少。囊泡形成机制可以聚集在纯化的致密溶酶体上，启动出芽，介导吞噬溶酶体的分解，并参与自溶酶体重组(ALR)产生的小管的形成和裂变。遗传性痉挛性截瘫蛋白SPG11、SPG15和AP5参与溶酶体膜循环。磷脂酰肌醇3-磷酸(PtdIns3P)、磷脂酰肌醇4-磷酸(PtdIns4P)、磷脂酰肌醇4,5-二磷酸(PtdIns(4,5)P2)和磷脂酰肌醇3,4,5-三磷酸(PtdIns(3,5)P2)参与溶酶体通过囊泡或管状中间体的膜出口，但其下游效应物尚不清楚。ARF-pi4kii β阳性囊泡可能调节PtdIns3P信号，促进溶酶体小管分裂。动力蛋白超家族蛋白在许多情况下介导分裂，动力蛋白2在肝细胞脂质吞噬过程中切断ALR小管。然而，作用于溶酶体的裂解分子仍有待鉴定。亨廷顿蛋白，延伸因子，蛋白磷酸酶2A的一个亚基，信号激酶TOR1 (HEAT)重复序列是由短环连接的两亲性α-螺旋对阵列。它们存在于功能多样的真核蛋白中。HEAT以反平行方式排列并堆叠以形成具有大表面积的结构柔性和高弹性螺线管。这些特性对于在各种细胞内环境下形成支架和桥接蛋白质-蛋白质相互作用是重要的。HPO-27在溶酶体裂变中的功能模型（Credit: Nature）该研究确定了HPO-27是一个溶酶体裂解分子。HPO-27作为RAB-7效应物被募集到溶酶体中，介导膜收缩和断裂。因此，HPO-27维持溶酶体的形状、结构完整性和降解功能，这对动物的发育和长寿至关重要。人类同源物MROH1也与溶酶体相关，促进小管裂变。该研究表明HPO-27和MROH1自组装介导膜收缩和断裂。中国科学院生物物理研究所王晓晨研究员和冯巍研究员为本文的共同通讯作者。云南大学和中国科学院生物物理研究所联合培养李乐涛博士、中国科学院生物物理研究所刘希璐博士、博士生杨珊珊为共同第一作者。原文链接https://www.nature.com/articles/s41586-024-07249-8责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述