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Vesicle trafficking and pathways to neurodegeneration
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2021-08-21 , DOI: 10.1186/s13024-021-00480-1
Craig Blackstone ₁ , Fiona Elwood ₂ , Helene Plun-Favreau ₃ , Patrick A Lewis _{3,

4}

Affiliation

Neurodegenerative diseases, encompassing a diverse range of inherited and sporadic disorders characterised by progressive loss of relatively discrete neuronal populations, are a significant and increasing challenge to human health and the global economy [1]. Despite significant advances in our understanding of the underlying ætiology of diseases such as Alzheimer’s, Parkinson’s and Huntington’s, and intense efforts targeting the development of disease-modifying therapies for these disorders, for the majority of people living with neurodegenerative conditions the prognosis remains poor [2,3,4]. Improving our knowledge of the underlying causes of neuronal loss in these disorders with the goal of developing novel disease-modifying therapies is thus a top priority for research, patient and care-giver communities.

An area of cell biology that has emerged over the past two decades as a key contributor to the events that lead to neuronal cell death across the whole spectrum of neurodegenerative disease is that of vesicle trafficking [5]. Regulating the formation and degradation of vesicles, what goes in to them, where they go, and what happens to them is a fundamental function required for cell viability [6], and so it is perhaps not surprising that dysfunction of these dynamic systems can result in disease. Driven in part by rapid advances in human genetics, it has become very clear that neuronal cells are exquisitely sensitive to disruption of vesicle trafficking – with a wide range of neurodegenerative diseases caused by specific mutations in genes that contribute to the regulation of vesicle trafficking.

To capitalise on the rapid increase in research on vesicle biology in neurodegeneration, a three-day virtual meeting on “Vesicle trafficking and pathways to neurodegeneration” was hosted by Wellcome Connecting Science from May 17th to 19th 2021 (Fig. 1). The goal of this meeting was to bring together researchers from a broad spectrum of neurodegenerative disorders research, including students, early career researchers and established scientists, spanning clinical, genetic, cellular, in vivo, translational biology, and industry in order to break down some of the barriers between these various groups – searching for areas of common interest and opportunities to accelerate the progress of research.

Like many conferences scheduled over the past 18 months, the original aim was for the meeting to be held in person (in this case at the Wellcome Genome Campus in Hinxton). Circumstances related to the covid-19 pandemic, however, did not allow this and so the meeting was held as a virtual event – with the positive outcome that this opened up attendance throughout the world in a way that would not have been possible in person. The meeting was attended by over 230 researchers, representing 23 different countries, and was divided into sessions covering five broadly-defined areas related to vesicle trafficking (Fig. 2), alongside a session focused on the neurogenetics of vesicle trafficking as well as a drug discovery panel discussing how we can drug vesicle trafficking processes within the brain.

The conference was bookended by two outstanding keynote lectures, the first from Jennifer Lippincott-Schwartz (Howard Hughes Medical Institute Janelia Research Campus), describing with exquisite resolution the trafficking of proteins from the endoplasmic reticulum through to the Golgi apparatus [7], and the second by Pietro de Camilli (Yale University School of Medicine and Howard Hughes Medical Institute) covering his recent investigations into disruption of vesicle trafficking linked to neurodegenerative disease gene mutations – most notably those linked to VPS13D [8].

The intervening sessions showcased some incredibly exciting published and unpublished research, highlighting both the breadth and depth of research into vesicular dysfunction in neurodegeneration. One aspect that became obvious quite quickly was that the somewhat arbitrary dividing lines between different domains of vesicular transport within the cell that was used to demarcate the five biology sessions were just that – somewhat arbitrary. Across all of the sessions one could observe common themes, and indeed common genetic contributors, often acting across multiple different disorders. Making sense of this, and in particular the commonalities and contrasting ætiologies between, for example, vesicular dysfunction contributing to frontal temporal dementia and that found in amyotrophic lateral sclerosis (frequently with closely-related genetic defects) [9], has the potential to reveal important insights into why individuals develop one form of brain disease rather than another.

Two key challenges emerged from the presentations and discussions during the conference. Neither of these are unique to neurodegeneration, but are acutely obvious and – in some respects – perhaps exacerbated by the complexities of studying disorders of the central nervous system. First, the sheer volume of genetic and clinical data that is now being generated across neurological diseases presents a huge task for functional biology. As we develop an ever more detailed understanding of population-wide genetic risk, through large scale sequencing, association studies, and expression analyses, there is an ever longer list of potential risk genes to investigate and comprehend [10]. With regard to this, it was striking that a majority of the presentations at the meeting involved investigating monogenic aspects of neurodegenerative disease, whether that be the ultrastructure of Huntington disease intracellular inclusions and how these disrupt endolysosomal function [11], or the function of Leucine Rich Repeat Kinase 2 in responding to lysosomal damage [12] in Parkinson disease (to cite two examples of topics covered by short talks at the meeting). Moving from a monogenic-centric approach to the cell biology of neurodegeneration to making sense of the complexities of common genetic risk for neurodegeneration at a functional level is a gargantuan task, and one that is only just beginning to be confronted.

The second major challenge is that of translating advances in our understanding of the cellular processes driving disease into clinical benefits for patients. Despite some notable recent successes, for example recent advances in targeting spinal muscular atrophy [13], the development of drugs that modify central nervous system disorders, and in particular neurodegenerative diseases, has proved extremely challenging [14, 15]. Taking dementia as a case study, the last two decades have witnessed a number of promising preclinical drug candidates failing in large human trials [16]. Exploiting the increasing body of knowledge relating to vesicle trafficking dysfunction in neurodegeneration presents some major challenges, not least determining how to achieve specificity in the central nervous system, and how to measure biological activity in a human. The inherent challenges of drugging these pathways may require new approaches in compound screening, model development, the science of therapeutics and biomarker discovery (the subject of some discussion during the panel held as part of this conference). These challenges, however, should not distract from the opportunities presented by the increasing diversity of targets for neurodegeneration and the new insights into disease biology provided by research into this area.

The overriding impression from this conference, taking into account all of the talks and posters presented at the meeting, is a feeling of optimism for the future, in particular with regard to the power of technology to drive insights into the fundamental biology of vesicle trafficking and into understanding disease ætiology.

Across the programme, we were witness to some outstanding examples of the application of high-content screening [17] and cryoelectron tomography [18], providing a high volume of information and close to atomic resolution. Coupled with deep learning approaches applied to increasingly large genetic and biological datasets [19], this heralds a new era in our understanding of the events regulating vesicle trafficking in the cells of the central nervous system. As novel approaches to in silico imaging allow the refinement of experimental models [20], and proteome-wide investigations begin to achieve a level of comprehensiveness comparable to nucleic acid-based genomic analyses [21], this is clearly an important area of biology to follow closely over the coming years.

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The meeting organisers would like to thank the staff at Wellcome Connecting Science who made this conference possible, in particular Amanda Fletcher and Dr. Jane Murphy, as well as all of the speakers, poster presenters and delegates who attended the conference.

The Vesicle trafficking and pathways to neurodegeneration meeting was funded and supported by Wellcome Connecting Science. HPF and PAL are supported by the Aligning Science across Parkinson’s research network (grant ASAP 0478) and by the Medical Research Council (programme grant MR/N026004/1).

Affiliations

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Craig Blackstone
Novartis Institute for Biomedical Research, 250 Massachusetts Ave, Cambridge, MA, 02139, USA
Fiona Elwood
UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
Helene Plun-Favreau & Patrick A. Lewis
Royal Veterinary College, University of London, London, NW1 0TU, UK
Patrick A. Lewis

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The manuscript was drafted by PAL, and then commented upon and edited by all authors. All authors read and approved the final manuscript.

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Correspondence to Patrick A. Lewis.

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Fiona Elwood is an employee of Novartis.

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Blackstone, C., Elwood, F., Plun-Favreau, H. et al. Vesicle trafficking and pathways to neurodegeneration. Mol Neurodegeneration 16, 56 (2021). https://doi.org/10.1186/s13024-021-00480-1

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Received: 20 July 2021
Accepted: 03 August 2021
Published: 21 August 2021
DOI: https://doi.org/10.1186/s13024-021-00480-1

中文翻译：

囊泡运输和神经变性途径

神经退行性疾病包括各种以相对离散的神经元群体逐渐丧失为特征的遗传性和散发性疾病，是对人类健康和全球经济的重大且日益严峻的挑战 [1]。尽管我们对阿尔茨海默氏症、帕金森氏症和亨廷顿氏症等疾病的潜在病因学的理解取得了重大进展，并且为开发针对这些疾病的疾病修饰疗法做出了巨大努力，但对于大多数患有神经退行性疾病的人来说，预后仍然很差 [2 ,3,4]。因此，为了开发新的疾病缓解疗法，提高我们对这些疾病中神经元丢失的根本原因的了解是研究、患者和护理人员社区的首要任务。

在过去二十年中出现的细胞生物学领域是囊泡运输 [5]，它是导致整个神经退行性疾病范围内神经元细胞死亡事件的关键因素。调节囊泡的形成和降解、进入囊泡的物质、它们的去向以及它们发生的事情是细胞活力所需的基本功能 [6]，因此这些动态系统的功能障碍可能导致在疾病中。部分受人类遗传学快速进步的推动，神经元细胞对囊泡运输的中断非常敏感——许多神经退行性疾病是由有助于调节囊泡运输的基因的特定突变引起的。

为了利用神经变性中囊泡生物学研究的快速增长，Wellcome Connecting Science 于 2021 年 5 月 17 日至 19 日举办了为期三天的“囊泡运输和神经变性途径”虚拟会议（图 1）。这次会议的目的是汇集来自广泛的神经退行性疾病研究领域的研究人员，包括学生、早期职业研究人员和知名科学家，跨越临床、遗传、细胞、体内、转化生物学和行业，以打破一些这些不同群体之间的障碍——寻找共同感兴趣的领域和机会来加速研究的进展。

与过去 18 个月安排的许多会议一样，最初的目的是让会议亲自举行（在本例中是在 Hinxton 的 Wellcome Genome Campus）。然而，与 covid-19 大流行相关的情况不允许这样做，因此会议以虚拟活动的形式举行——取得了积极的成果，这以一种不可能亲自参加的方式在全世界开放了与会者。代表 23 个不同国家的 230 多名研究人员参加了这次会议，会议分为五个与囊泡运输相关的广义领域（图 2），还有一个会议侧重于囊泡运输的神经遗传学以及一种药物发现小组讨论我们如何在大脑内进行药物囊泡运输过程。

会议以两场出色的主题演讲结束，第一场来自 Jennifer Lippincott-Schwartz（霍华德休斯医学研究所 Janelia 研究园区），以精致的分辨率描述了蛋白质从内质网到高尔基体的运输 [7]，以及第二篇文章由 Pietro de Camilli（耶鲁大学医学院和霍华德休斯医学研究所）撰写，涵盖了他最近对与神经退行性疾病基因突变相关的囊泡运输中断的调查——最引人注目的是与 VPS13D 相关的那些 [8 ]。

其间的会议展示了一些令人难以置信的令人兴奋的已发表和未发表的研究，突出了神经变性中囊泡功能障碍研究的广度和深度。一个很快变得很明显的方面是，用于划定五个生物学阶段的细胞内不同囊泡运输区域之间的分界线有点武断——有点武断。在所有的会议中，人们可以观察到共同的主题，甚至是共同的遗传因素，它们通常作用于多种不同的疾病。理解这一点，特别是之间的共同点和对比 ætiologies，例如，

会议期间的演讲和讨论中出现了两个主要挑战。这些都不是神经变性所独有的，而是非常明显的，并且 - 在某些方面 - 可能因研究中枢神经系统疾病的复杂性而加剧。首先，目前在神经系统疾病中产生的大量遗传和临床数据为功能生物学提出了一项艰巨的任务。随着我们通过大规模测序、关联研究和表达分析对全人群遗传风险的了解越来越详细，需要调查和理解的潜在风险基因列表越来越长 [10]。关于这一点，令人惊讶的是，会议上的大多数演讲都涉及调查神经退行性疾病的单基因方面，，或富亮氨酸重复激酶 2 在响应帕金森病溶酶体损伤 [12] 中的功能（引用会议上简短谈话所涵盖主题的两个例子）。从以单基因为中心的方法到神经变性的细胞生物学，再到在功能水平上理解神经变性常见遗传风险的复杂性，是一项艰巨的任务，而且才刚刚开始面临。

第二个主要挑战是将我们对驱动疾病的细胞过程的理解进展转化为对患者的临床益处。尽管最近取得了一些显着的成功，例如最近在针对脊髓性肌萎缩症 [13] 方面取得的进展，但事实证明，改变中枢神经系统疾病，特别是神经退行性疾病的药物的开发极具挑战性 [14, 15]。以痴呆症为例，过去二十年见证了许多有前途的临床前候选药物在大型人体试验中失败 [16]。利用越来越多的与神经变性囊泡运输功能障碍相关的知识体系提出了一些重大挑战，尤其是确定如何在中枢神经系统中实现特异性，以及如何测量人体的生物活性。对这些途径进行药物治疗的固有挑战可能需要在化合物筛选、模型开发、治疗科学和生物标志物发现方面采用新方法（作为本次会议的一部分举行的小组讨论的主题）。然而，这些挑战不应分散人们对神经变性靶标日益多样化所带来的机遇以及对该领域的研究提供的疾病生物学新见解的注意力。

考虑到会议上展示的所有演讲和海报，本次会议的压倒一切的印象是对未来的乐观情绪，特别是在技术的力量推动对囊泡运输的基础生物学的洞察力和了解疾病的病因学。

在整个计划中，我们见证了高内涵筛选 [17] 和低温电子断层扫描 [18] 应用的一些杰出示例，它们提供了大量信息并接近原子分辨率。结合应用于越来越大的遗传和生物数据集的深度学习方法 [19]，这预示着我们对调节中枢神经系统细胞囊泡运输的事件的理解进入了一个新时代。随着计算机成像的新方法允许改进实验模型 [20]，并且蛋白质组范围内的研究开始达到与基于核酸的基因组分析相媲美的综合性水平 [21]，这显然是生物学的一个重要领域在未来几年密切关注。

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下载参考资料

会议组织者要感谢 Wellcome Connecting Science 的工作人员使这次会议成为可能，特别是 Amanda Fletcher 和 Jane Murphy 博士，以及所有出席会议的演讲者、海报展示者和代表。

囊泡运输和神经变性途径会议由 Wellcome Connecting Science 资助和支持。HPF 和 PAL 得到帕金森研究网络对齐科学（尽快拨款 0478）和医学研究委员会（计划拨款 MR/N026004/1）的支持。

隶属关系

麻省总医院和哈佛医学院神经内科, Boston, MA, 02114, USA
克雷格·布莱克斯通
诺华生物医学研究所，250 Massachusetts Ave, Cambridge, MA, 02139, USA
菲奥娜埃尔伍德
伦敦大学学院皇后广场神经病学研究所，伦敦皇后广场，WC1N 3BG，英国
Helene Plun-Favreau & Patrick A. Lewis
伦敦大学皇家兽医学院，伦敦，NW1 0TU，英国
帕特里克 A. 刘易斯

作者

克雷格·布莱克斯通查看作者的出版物
也可以在PubMed Google Scholar中搜索此作者
Fiona Elwood查看作者的出版物
也可以在PubMed Google Scholar中搜索此作者
Helene Plun-Favreau查看作者的出版物
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帕特里克 A. 刘易斯查看作者的出版物
也可以在PubMed Google Scholar中搜索此作者

投稿

手稿由 PAL 起草，然后由所有作者评论和编辑。所有作者阅读并认可的终稿。

作者信息

不适用。

通讯作者

与 Patrick A. Lewis 的通信。

伦理批准和同意参与

不适用。

同意发表

不适用。

利益争夺

Fiona Elwood 是诺华公司的一名员工。

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施普林格·自然 (Springer Nature) 对已出版地图和机构隶属关系中的管辖权主张保持中立。

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