Frederik (Fred) Willem van Leeuwen (Amsterdam, 1949), a Dutch neurobiologist, passed away on January 13, 2021 after a period of illness. Fred was well known internationally for his contributions to the fields of neuropeptides and neurodegeneration, and in particular for his breakthrough discovery on frameshift mutants of ubiquitin (Ub) that are present in the neuritic plaques and neurofibrillary tangles that characterize Alzheimer’s disease (AD). This remarkable discovery provided the first compelling mechanistic evidence for the involvement of the Ub-proteasome system (UPS), the major intracellular proteolytic pathway, in AD pathogenesis. The evidence for the involvement of the UPS in neurodegeneration has grown ever since exponentially, and has engulfed literally all neurodegenerative disorders in different mechanisms of protein quality control.

Fred was trained in neurobiology at the Netherlands Institute for Brain Research, part of the Royal Netherlands Academy of Arts and Sciences (KNAW), in Amsterdam (PhD 1980; Thesis: ‘Light and electron microscopical immunocytochemical localization of neuropeptides in the rat brain’, promotor: Prof. Dr. D.F. Swaab, Vrije Universiteit, Amsterdam). There, he conducted research on neuropeptides and the brain hypothalamo-neurohypophyseal system. Of note are his pioneering studies on the extrahypothalamic localization of vasopressin (VP), oxytocin and other neuropeptides, the role of neuropeptide innervation of pituicytes in the release of VP and oxytocin in the neurohypophysis, and the specificity problems of immunocytochemistry. Importantly, he also carried out work on the Brattleboro rat, a natural knockout model for VP. The homozygous Brattleboro rat suffers from central diabetes insipidus due to a single base deletion in the VP peptide hormone precursor. This deletion causes a − 1 frameshift, and results in an abnormal VP precursor product that cannot enter the secretory pathway. Surprisingly, it was found that some solitary neurons in the brain of this knockout mouse display immunoreactivity for VP, and that the number of VP-positive cells in the brain increased progressively with age. Further investigation by Fred and his team revealed that this revertant phenotype was apparently caused by additional transcriptional dinucleotide deletions (ΔGA) occurring on simple repeat motifs (GAGAG) present in the VP gene. These dinucleotide deletions, generated by misreading of the genetic code, resulted in restoration of the wild-type (WT) reading frame and synthesis of a functional VP molecule.

Based on the observations in the Brattleboro rat, it was hypothesized that molecular misreading events of transcripts (there are no mutations in the coding gene) may also occur on dinucleotide repeat motifs present in other genes, and that such events might even contribute to age-related neurodegenerative disease. Interestingly, Fred’s team demonstrated that similar + 1 frameshift mutants could indeed be detected in the brains of patients with early onset AD and Down syndrome (the latter also exhibit AD-like brain pathology when middle-aged). In particular, a frameshift mutant of Ub, dubbed UBB^+ 1, was shown to accumulate as a neuropathological hallmark in these diseases. The frameshift results in addition of a 19 amino acids tail to the molecule which alters the ‘canonical’ C-terminal glycine residue of the molecule. In the WT molecule, this moiety is activated by the Ub-activating enzyme, E1, and is then covalently conjugated to the target proteins (and to previously conjugated Ub moieties) via an isopeptide bond (to the ε-NH₂ amino group of an internal Lys residue), signaling them for proteasomal degradation. The alteration in the C-terminal residue abrogates the conjugating ability of Ub. It was established that UBB^+ 1 is a dose-dependent inhibitor of the UPS, and that expression of UBB^+ 1 in experimental model systems results in phenotypes that are compatible with neurodegeneration. UBB^+ 1 was also detected in protein aggregates in an array of other neurodegenerative diseases, specifically in tauopathies (e.g., Pick’s disease), and polyglutamine repeat disorders (e.g., Huntington’s disease). It is plausible that UBB^+ 1 contributes to disease progression by influencing cellular quality control pathways (as while it cannot conjugate to target proteins signaling them for degradation, it can deplete intracellular Ub pools by being conjugated by WT Ub), and by modifying the aggregation and toxicity of other disease-associated proteins.

While the exact molecular origins of the + 1 frameshift mutants have remained elusive and the biological consequences of UBB^+ 1 expression remain to be explored in more detail, the findings suggested a novel mechanism of neurodegeneration that depends on the UPS. Extended Ub mutants have also been used as tools to selectively probe the Ub landscape in cells.

Fred was recruited in 2007 to the Maastricht University Department of Psychiatry and Neuropsychology, part of the School for Mental Health and Neuroscience at the Faculty of Health, Medicine and Life Sciences where he remained until his retirement in 2016. After his retirement, he remained active as a scientist and continued to publish on the UBB^+ 1 mutant.

All of us who had the honor of working with Fred remember him as an enthusiastic and engaged scientist and a friendly, loyal and supportive colleague. This was exemplified by his generous sharing of knowledge and resources. He invested a lot of his time in teaching and mentoring, and in organizing events that aimed to stimulate contacts between neuroscientists. For example, he organized international practical courses on Immunocytochemistry (EMBO) and on Molecular Neuroanatomy (ETP/ENA/IBRO), and was an initiator and driving force behind the Endo-Neuro-Psycho (ENP) meetings in the Netherlands, currently known as the Dutch Neuroscience Meetings. He remained fully devoted to his family and scientific work until his death. Fred and his frameshifting thinking will be deeply missed by his colleagues, trainees and friends.

Fred is survived by his wife Elly, his son Roelof and his daughters Sara and Hilde, and their children.

We thank Elly van Leeuwen, Gerard Boer and Dick Swaab for helpful suggestions.

Affiliations

1. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA

   Bert M. Verheijen

2. The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, 31096, Haifa, Israel

   Aaron Ciechanover

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Both authors wrote and approved the final manuscript.

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Correspondence to Bert M. Verheijen or Aaron Ciechanover.

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The authors declare that they have no competing interests.

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Verheijen, B.M., Ciechanover, A. Fred W. van Leeuwen (1949–2021). Mol Neurodegeneration 16, 20 (2021). https://doi.org/10.1186/s13024-021-00444-5

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• Published: 31 March 2021

• DOI: https://doi.org/10.1186/s13024-021-00444-5

中文翻译：

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弗雷德·范·列文（Fred W. van Leeuwen）（1949-2021）

荷兰神经生物学家Frederik（Fred）Willem van Leeuwen（阿姆斯特丹，1949年）在患病一段时间后于2021年1月13日去世。弗雷德（Fred）在神经肽和神经变性领域做出的贡献在国际上广为人知，尤其是他对泛素（Ub）移码突变体的突破性发现，这种突变存在于神经性斑块和神经原纤维缠结中，是阿尔茨海默氏病（AD）的特征。这一显着发现为Ub-蛋白酶体系统（UPS）（主要的细胞内蛋白水解途径）参与AD发病机理提供了首个令人信服的机制证据。自此以来，UPS参与神经退行性疾病的证据呈指数增长，并且已将所有神经退行性疾病完全吞噬了蛋白质质量控​​制的不同机制。

弗雷德（Fred）在阿姆斯特丹的皇家荷兰科学院（KNAW）的荷兰脑科学研究所接受了神经生物学的培训（PhD 1980;论文：“大鼠脑中神经肽的光电子显微镜免疫细胞化学定位”），发起人：阿姆斯特丹弗里耶大学DF Swaab博士教授。在那里，他对神经肽和大脑下丘脑-神经下垂系统进行了研究。值得注意的是，他在血管加压素（VP），催产素和其他神经肽的下丘脑外定位，神经肽的神经肽神经支配在神经垂体中VP和催产素释放中的作用以及免疫细胞化学的特异性问题方面的开创性研究。重要的是，他还对Brattleboro大鼠进行了研究，它是VP的自然基因剔除模型。纯合的Brattleboro大鼠由于VP肽激素前体中的单个碱基缺失而患有中枢性尿崩症。这种缺失导致− 1移码，并导致无法进入分泌途径的异常VP前体产物。出人意料的是，发现该敲除小鼠的大脑中一些孤立的神经元对VP表现出免疫反应性，并且大脑中VP阳性细胞的数量随着年龄的增长而逐渐增加。弗雷德及其小组的进一步研究表明，这种可逆表型显然是由VP基因中存在的简单重复基序（GAGAG）上发生的额外转录二核苷酸缺失（ΔGA）引起的。这些二核苷酸缺失是由于对遗传密码的误读而产生的，

根据Brattleboro大鼠的观察，假设转录物的分子误读事件（编码基因中没有突变）也可能发生在其他基因中存在的二核苷酸重复基序上，并且此类事件甚至可能会导致年龄增长。相关的神经退行性疾病。有趣的是，弗雷德（Fred）的研究小组证明，在患有早发性AD和唐氏综合症的患者的大脑中确实可以检测到类似的+ 1移码突变体（唐氏综合症在中年时也表现出类似AD的大脑病理）。特别是称为UBB ^{+ 1}的Ub移码突变体被证明在这些疾病中作为神经病理学标志蓄积。移码会在分子上增加19个氨基酸的尾巴，从而改变分子的“规范” C末端甘氨酸残基。在WT分子，这部分是由泛素激活酶，E1活化，然后共价经由异肽键缀合到靶蛋白（以及先前结合的泛素部分）（给ε-NH ₂氨基的内部Lys残基），提示它们发生蛋白酶体降解。C末端残基的改变消除了Ub的结合能力。已经确定，UBB ^{+ 1}是UPS的剂量依赖性抑制剂，并且UBB ^{+ 1的}表达实验模型系统中的结果导致与神经变性兼容的表型。在其他一系列神经退行性疾病的蛋白质聚集体中也检测到了UBB ^{+ 1}，特别是在taopathies（例如，匹克氏病）和多谷氨酰胺重复性疾病（例如，Huntington病）中。可能的是，UBB ^{+ 1}通过影响细胞质量控制途径（虽然无法与信号蛋白降解的靶蛋白结合，但可以通过与WT Ub结合来耗尽细胞内Ub库）来促进疾病进展。和其他疾病相关蛋白的毒性。

虽然+ 1移码突变体的确切分子起源仍然难以捉摸，而且UBB ^{+ 1}表达的生物学后果仍有待更详细地探讨，但研究结果表明，依赖于UPS的神经退行性疾病的新机制。扩展的Ub突变体也已被用作选择性探测细胞中Ub景观的工具。

弗雷德（Fred）于2007年被招募至马斯特里赫特大学精神病与神经心理学系，该大学隶属于卫生，医学与生命科学学院心理健康与神经科学学院，一直任职至2016年退休。退休后，他仍然活跃作为一名科学家，并继续发表有关UBB ^{+ 1}突变体的文章。

我们所有人都有幸与Fred一起工作，我们都将他铭记为热情，敬业的科学家以及友好，忠诚和支持性的同事。他慷慨地分享知识和资源便证明了这一点。他将大量时间用于教学和指导，以及组织旨在激发神经科学家之间联系的活动。例如，他组织了有关免疫细胞化学（EMBO）和分子神经解剖学（ETP / ENA / IBRO）的国际实践课程，并且是在荷兰举行的Endo-Neuro-Psycho（ENP）会议（目前称为“会议”）的发起者和推动力。荷兰神经科学会议。直到他去世，他一直全心全意地致力于家庭和科学工作。弗雷德（Fred）和他的转移思维将被他的同事，受训者和朋友深深地怀念。

弗雷德的妻子艾莉（Elly），儿子罗洛夫（Roelof）和女儿萨拉（Sara）和希尔德（Hilde）及其子女得以幸存。

我们感谢Elly van Leeuwen，Gerard Boer和Dick Swaab提出的有益建议。

隶属关系

1. 美国南加州大学伦纳德·戴维斯老年医学学院，美国加利福尼亚州90089

   伯特·M·弗海金

2. 以色列-以色列技术学院拉帕波特医学院和研究所，31096，以色列海法

   亚伦·西查诺佛

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Verheijen，BM，Ciechanover，A. Fred W. van Leeuwen（1949-2021）。摩尔神经变性 16， 20（2021）。https://doi.org/10.1186/s13024-021-00444-5

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