HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease,Molecular Neurodegeneration

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HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2024-10-25 , DOI: 10.1186/s13024-024-00768-y
Ellen A. Albagli, Anna Calliari, Tania F. Gendron, Yong-Jie Zhang

In 2006, TAR DNA-binding protein of 43 kDa (TDP-43) was discovered as the major ubiquitinated and aggregated protein in approximately 95% of amyotrophic lateral sclerosis (ALS) cases and 45% of frontotemporal lobar degeneration (FTLD) cases [1]. Since then, TDP-43 pathology has been identified in Alzheimer’s disease (AD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and other neurodegenerative diseases [2]. This discovery initiated copious studies uncovering the pathomechanisms through which TDP-43, an RNA-binding protein with roles in alternative splicing, causes neurodegeneration [2] – chief among them, its loss of function owing to its aggregation in the cytoplasm and concurrent depletion from the nucleus.

TDP-43 proteinopathies share clinical, genetic, and pathological features, and this is particularly true of frontotemporal dementia (FTD) and ALS. While no treatments for FTD, ALS, or other TDP-43 proteinopathies yet exist, developing effective therapies for these fatal neurodegenerative diseases would benefit from biomarkers that facilitate an early and accurate diagnosis. Indeed, therapies are expected to be most effective when initiated early in the disease course. Biomarkers that identify the underlying pathology of patients with FTD in life would also aid in selecting appropriate participants for clinical trials targeting TDP-43 proteinopathy. As patients with behavioral variant FTD are essentially just as likely to develop TDP-43 or tau pathology, biomarkers that inform the presence of TDP-43 pathology would be particularly useful for this group, as would patients with AD who often develop mixed pathologies [3]. Although studies have examined whether TDP-43 itself could fulfill these biomarker needs, multiple efforts in detecting pathological TDP-43 species in biofluids have so far been unsuccessful [4]. Nevertheless, an exciting avenue being pursued harnesses the consequences of TDP-43 loss of function; more specifically, TDP-43’s inability to repress the splicing of non-conserved cryptic exons (CE) [5]. This engenders the production of novel RNA isoforms bearing non-conserved intronic sequences that often introduce frameshifts, premature stop codons, or premature polyadenylation sequences. For example, inclusion of a CE in STMN2 mRNA produces a truncated stathmin-2 protein at the expense of its full-length counterpart, whereas inclusion of a CE in UNC13A mRNA reduces UNC13A protein expression (Fig. 1A) [6]. While cryptic RNAs including STMN2-CE and UNC13A-CE have been detected in postmortem brain tissue [6], they have yet to be detected in biofluids, hindering their application for biomarker development. Perhaps most pertinent to biomarker development, consequently, are the cryptic transcripts that generate de novo proteins.

Seddighi et al. recently generated an atlas of CEs utilizing TDP-43-depleted human induced pluripotent stem cell (iPSC)-derived neurons to model nuclear TDP-43 loss of function. Notably, some CEs were found to interact with ribosomes, suggesting there may be active translation of these non-conserved sequence-retaining transcripts. Indeed, by combining transcriptomics with proteomics, they identified 65 cryptic peptides, more than half of which were predicted to incorporate an in-frame CE [7]. Therefore, Seddighi and colleagues developed antibodies for two such CE-containing peptides, HDGFL2-CE and MYO18A-CE. The hepatoma derived growth factor 2 (HDGFL2), a histone-binding protein that regulates chromatin accessibility and recruits regulatory factors to assist in DNA damage repair, is ubiquitously expressed throughout the central nervous system (CNS) [7]. When TDP-43 becomes dysfunctional, an in-frame CE is incorporated between exons 5 and 6 of the mature HDGFL2 transcript, thereby producing HDGFL2-CE, a stable cryptic peptide (Fig. 1B) [7]. The second CE-containing peptide, Myosin XVIIIA (MYO18A), is a cytoskeletal protein moderately expressed in the CNS that modulates cell structure and migration [7]. Both HDGFL2 and MYO18A CE-containing transcripts were found to be significantly elevated in postmortem frontal cortex tissues from FTLD-TDP patients, and their cryptic peptides were detected in cerebrospinal fluid (CSF) from patients with ALS or FTD, suggesting these cryptic peptides and others may serve as stable fluid biomarkers of TDP-43 dysfunction [7].

Similarly to the above-mentioned work, Irwin and colleagues sifted through RNA sequencing datasets from TDP-43-depleted HeLa cells and iPSC-derived motor neurons, likewise identifying HDGFL2 transcripts harboring an in-frame CE [8]. Using a novel anti-HDGFL2-CE antibody and postmortem motor cortex and hippocampal tissues from ALS and FTLD-TDP cases, Irwin et al. ascertained that HDGFL2-CE was specifically detected in neurons depleted of nuclear TDP-43. Towards detecting HDGFL2-CE in biofluids, they developed a HDGFL2-CE immunoassay allowing them to measure HDGFL2-CE in CSF and plasma. Compared to controls, CSF HDGFL2-CE was higher in patients with sporadic ALS and in presymptomatic and symptomatic C9orf72 repeat expansion carriers [8]. These findings are indeed encouraging, but as with all biomarkers, will require validation using larger cohorts and rigorous analyses.

To establish if HDGFL2-CE abundance can be used to gauge TDP-43 pathology and dysfunction, Calliari et al. investigated whether HDGFL2-CE is preferentially expressed in neuroanatomical regions with TDP-43 proteinopathy. To this end, they availed well-characterized cohorts of FTLD-TDP and AD-TDP postmortem cases coupled with a novel HDGFL2-CE immunoassay [9]. Compared to controls, they observed significantly higher HDGFL2-CE in the frontal cortex and amygdala in FTLD-TDP cases, and in the amygdala of AD cases with TDP-43 pathology. Of importance, the presence of HDGFL2-CE distinguished cases with and without TDP-43 pathology with good to excellent discriminatory ability. Furthermore, both HDGFL2-CE transcripts and HDGFL2-CE proteins positively correlated with phosphorylated TDP-43, a pathological trait of TDP-43 proteinopathy [9]. These findings demonstrate that HDGFL2-CE is a sensitive reporter of TDP-43 pathology in the CNS, and corroborate the use of CSF HDGFL2-CE as a surrogate marker of TDP-43 pathology and dysfunction [9].

Given the present dearth of TDP-43-associated biomarkers, continued investigations on HDGFL2-CE and other cryptic peptides are warranted. Although Seddighi et al. availed proteomic analyses to identify cryptic peptides in CSF from ALS/FTD patients [7], more sensitive quantitative proteomic approaches are required to ascertain whether these cryptic peptides are elevated in ALS/FTD. Nevertheless, validating HDGFL2-CE as a biomarker for TDP-43 dysfunction would benefit from more practical methods, such as the use of highly specific and sensitive immunoassays. Such validation studies would also require the quantification of HDGFL2-CE concentrations in CSF or plasma from large, thoroughly-characterized cross-sectional and longitudinal cohorts with comprehensive clinical data and, ideally, autopsy-confirmed pathology. As optimized HDGFL2-CE assays become available, they are expected to enable the early detection of TDP-43 dysfunction in presymptomatic, prodromal, and clinical stages of disease, thereby facilitating the recruitment of participants in prevention and early treatment trials for therapies targeting aspects of TDP-43 pathophysiology. This notion is bolstered by the fact that Irwin et al. detected HDGFL2-CE in CSF from presymptomatic and symptomatic C9orf72 mutation carriers [8]. Although the studies discussed here reveal HDGFL2 is misspliced upon TDP-43 dysfunction [7,8,9], HDGFL2 splicing may be modulated by other proteins, which could confound its use as a marker for TDP-43 pathology and dysfunction. As such, despite the strong correlation between pathological TDP-43 and HDGFL2-CE in postmortem tissues supporting its utility as a TDP-43 marker [9], coupling HDGFL2-CE with a panel of other cryptic peptides including MYO18A, AGRN, and CAMK2B [7] warrants consideration as it could improve our confidence in accurately detecting TDP-43 dysfunction. It is thus worth noting that detection methods such as nucleic acid linked immuno-sandwich assays (NULISA) permit the simultaneous measurement of multiple cryptic peptides [10]. In tandem with these efforts, alternative biomarkers for identifying individuals with TDP-43 pathology are emerging.

As the field further probes the implications of cryptic peptides in FTD and ALS, investigating TDP-43 dysfunction in other TDP-43 proteinopathies should be taken into account. For example, muscle biopsies of patients with inclusion body myositis exhibit TDP-43 aggregates, nuclear TDP-43 clearance, and the inclusion of CEs in mRNA transcripts, including HDGFL2 [11]. Recent work has also identified TDP-43-mediated misspliced cryptic transcripts, such as STMN2, UNC13A, and HDGFL2 in AD and LATE [9, 12,13,14] suggesting that cryptic peptides as markers of TDP-43 dysfunction are relevant not only to ALS, FTD, AD, and LATE, but also to other neurodegenerative disorders with mixed pathologies such as Lewy body dementia, chronic traumatic encephalopathy, and other AD-related dementias.

As we further examine the utility of HDGLF2-CE as a biomarker, the functions of HDGFL2-CE and other cryptic proteins should be elucidated. Seddighi et al. found that HDGFL2-CE alters the HDGFL2 interactome, with HDGFL2-CE displaying increased interactions with RNA-binding proteins and decreased interactions with cytoskeletal proteins, suggesting that HDGFL2-CE induces both toxic gains and losses-of-function and may thus influence disease onset and progression [7]. Deciphering the pathomechanisms through which cryptic exon inclusions in transcripts contribute to neurodegeneration will broaden our understanding of disease pathogenesis and may provide a more targeted approach in treating TDP-43 proteinopathies.

Not applicable.

AD:: Alzheimer’s disease
ALS:: Amyotrophic lateral sclerosis
CE:: Cryptic exon
CNS:: Central nervous system
CSF:: Cerebrospinal fluid
FTD:: Frontotemporal dementia
FTLD:: Frontotemporal lobar degeneration
HDGFL2:: Hepatoma derived growth factor
iPSC:: Induced pluripotent stem cell
LATE:: Limbic-predominant age-related TDP-43 encephalopathy
MYO18A:: Myosin XVIIIA
NULISA:: Nucleic acid linked immuno-sandwich assay
TDP-43:: TAR DNA-binding protein of 43 kDa

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The authors were supported by the Target ALS Foundation (Y.-J.Z.), the National Institutes of Health/National Institute on Aging [(R01AG085307: Y.-J.Z.); (P30AG062677: T.F.G.); and (U19AG063911: T.F.G.)], the National Institutes of Health/National Institute of Neurological Disorders and Stroke [(P01NS084974: Y.-J.Z and T.F.G.); (R01NS117461: Y.-J.Z. and T.F.G.); (R01 NS121125: T.F.G.); and (R21NS127331: Y.-J.Z.)].

Authors and Affiliations

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
Ellen A. Albagli, Anna Calliari, Tania F. Gendron & Yong-Jie Zhang
Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA
Tania F. Gendron & Yong-Jie Zhang

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All authors wrote and approved the final manuscript.

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Correspondence to Tania F. Gendron or Yong-Jie Zhang.

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Competing interests

E.A.A., A.C., T.F.G., and Y.-J.Z. participated in the discovery and validation of HDGFL2-CE, authoring prior publications [7, 9].

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Albagli, E.A., Calliari, A., Gendron, T.F. et al. HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease. Mol Neurodegeneration 19, 79 (2024). https://doi.org/10.1186/s13024-024-00768-y

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Received: 07 August 2024
Accepted: 11 October 2024
Published: 25 October 2024
DOI: https://doi.org/10.1186/s13024-024-00768-y

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Keywords

Amyotrophic lateral sclerosis
Biomarkers
Cerebrospinal fluid
Cryptic peptide
Frontotemporal dementia
Hepatoma derived growth factor 2
Neurodegeneration
TAR DNA-binding protein 43

中文翻译：

HDGFL2 隐性蛋白：神经退行性疾病检测和诊断的门户

2006 年，在大约 95% 的肌萎缩侧索硬化症（ALS）病例和 45% 的额颞叶变性（FTLD）病例中，发现 43 kDa 的 TAR DNA 结合蛋白（TDP-43）是主要的泛素化和聚集蛋白 [1]。从那时起，TDP-43 病理学已在阿尔茨海默病（AD）、边缘为主的年龄相关性 TDP-43 脑病（LATE）和其他神经退行性疾病中被发现 [2]。这一发现引发了大量研究，揭示了 TDP-43（一种在选择性剪接中发挥作用的 RNA 结合蛋白）导致神经退行性变的病理机制 [2]——其中最主要的是，由于在细胞质中的聚集和细胞核的并发耗竭，它的功能丧失。

TDP-43 蛋白病具有临床、遗传和病理特征，额颞叶痴呆（FTD）和 ALS 尤其如此。虽然尚不存在针对 FTD、ALS 或其他 TDP-43 蛋白病的治疗方法，但为这些致命的神经退行性疾病开发有效的疗法将受益于有助于早期准确诊断的生物标志物。事实上，预计在病程早期开始治疗最有效。识别 FTD 患者在生活中潜在病理的生物标志物也将有助于为针对 TDP-43 蛋白病的临床试验选择合适的参与者。由于行为变异型 FTD 患者发生 TDP-43 或 tau 病变的可能性基本相同，因此告知 TDP-43 病变存在的生物标志物对这组患者特别有用，经常出现混合病变的 AD 患者也特别有用 [3]。尽管研究已经检查了 TDP-43 本身是否能满足这些生物标志物需求，但迄今为止，检测生物体液中病理性 TDP-43 物种的多种努力均未成功 [4]。然而，正在寻求的一条令人兴奋的途径是利用 TDP-43 功能丧失的后果;更具体地说，TDP-43 无法抑制非保守隐匿外显子（CE）的剪接 [5]。这产生了带有非保守内含子序列的新型 RNA 亚型，这些序列通常会引入移码、过早终止密码子或过早的多聚腺苷酸化序列。例如，在 STMN2 mRNA 中加入 CE 会产生截短的 stathmin-2 蛋白，而牺牲其全长对应物，而在 UNC13A mRNA 中加入 CE 会降低 UNC13A 蛋白的表达（图 1A）[6]。虽然已在死后脑组织中检测到包括 STMN2-CE 和 UNC13A-CE 在内的隐蔽 RNA [6]，但它们尚未在生物流体中检测到，这阻碍了它们在生物标志物开发中的应用。因此，也许与生物标志物开发最相关的是产生从头蛋白的神秘转录本。

Seddighi 等人最近利用 TDP-43 耗尽的人类诱导多能干细胞（iPSC）衍生的神经元生成了一份 CE 图谱，以模拟核 TDP-43 功能丧失。值得注意的是，发现一些 CE 与核糖体相互作用，表明这些非保守序列保留转录本可能存在活性翻译。事实上，通过将转录组学与蛋白质组学相结合，他们鉴定了 65 种隐性肽，其中一半以上被预测为包含框内 CE [7]。因此，Seddighi 及其同事开发了针对两种此类含 CE 的肽 HDGFL2-CE 和 MYO18A-CE 的抗体。肝癌衍生生长因子 2 （HDGFL2）是一种组蛋白结合蛋白，可调节染色质可及性并募集调节因子以协助 DNA 损伤修复，在整个中枢神经系统（CNS）中普遍表达 [7]。当 TDP-43 功能障碍时，成熟 HDGFL2 转录本的外显子 5 和 6 之间掺入框内 CE，从而产生稳定的隐性肽 HDGFL2-CE（图 1B）[7]。第二种含 CE 的肽，肌球蛋白 XVIIIA （MYO18A），是一种在 CNS 中适度表达的细胞骨架蛋白，可调节细胞结构和迁移 [7]。发现含 HDGFL2 和 MYO18A CE 的转录本在 FTLD-TDP 患者死后额叶皮层组织中显著升高，并且在 ALS 或 FTD 患者的脑脊液（CSF）中检测到它们的隐匿肽，表明这些隐蔽肽和其他肽可能是 TDP-43 功能障碍的稳定液体生物标志物 [7]。

与上述工作类似，Irwin 及其同事筛选了来自 TDP-43 耗尽的 HeLa 细胞和 iPSC 衍生的运动神经元的 RNA 测序数据集，同样鉴定了携带框内 CE 的 HDGFL2 转录本 [8]。Irwin 等人使用一种新的抗 HDGFL2-CE 抗体和来自 ALS 和 FTLD-TDP 病例的死后运动皮层和海马组织，确定 HDGFL2-CE 在耗尽核 TDP-43 的神经元中被特异性检测到。为了检测生物体液中的 HDGFL2-CE，他们开发了一种 HDGFL2-CE 免疫测定法，使他们能够测量 CSF 和血浆中的 HDGFL2-CE。与对照组相比，散发性 ALS 患者以及症状前和症状前 C9orf72 重复扩增携带者的 CSF HDGFL2-CE 更高 [8]。这些发现确实令人鼓舞，但与所有生物标志物一样，需要使用更大的队列和严格的分析进行验证。

为了确定 HDGFL2-CE 丰度是否可用于测量 TDP-43 病理和功能障碍，Calliari 等人研究了 HDGFL2-CE 是否优先在 TDP-43 蛋白病的神经解剖区域表达。为此，他们利用了特征明确的 FTLD-TDP 和 AD-TDP 尸检病例队列，以及一种新的 HDGFL2-CE 免疫测定 [9]。与对照组相比，他们在 FTLD-TDP 病例的额叶皮层和杏仁核以及具有 TDP-43 病理的 AD 病例的杏仁核中观察到 HDGFL2-CE 显着升高。重要的是，HDGFL2-CE 的存在区分了有和没有 TDP-43 病理的病例，具有良好到优秀的鉴别能力。此外，HDGFL2-CE 转录本和 HDGFL2-CE 蛋白都与磷酸化的 TDP-43 呈正相关，这是 TDP-43 蛋白病的一种病理特征 [9]。这些发现表明 HDGFL2-CE 是 CNS 中 TDP-43 病理的敏感报告基因，并证实了使用 CSF HDGFL2-CE 作为 TDP-43 病理和功能障碍的替代标志物 [9]。

鉴于目前缺乏 TDP-43 相关生物标志物，有必要对 HDGFL2-CE 和其他隐性肽进行持续研究。尽管 Seddighi 等人利用蛋白质组学分析来识别 ALS/FTD 患者脑脊液中的隐性肽 [7]，但需要更灵敏的定量蛋白质组学方法来确定这些隐性肽在 ALS/FTD 中是否升高。尽管如此，验证 HDGFL2-CE 作为 TDP-43 功能障碍的生物标志物将受益于更实用的方法，例如使用高度特异性和敏感性的免疫测定。此类验证研究还需要量化 CSF 或血浆中 HDGFL2-CE 浓度，这些浓度来自大型、全面表征的横断面和纵向队列，具有全面的临床数据，理想情况下是尸检证实的病理学。随着优化的 HDGFL2-CE 检测的推出，它们有望在疾病的症状前、前驱和临床阶段及早发现 TDP-43 功能障碍，从而促进招募参与者进行预防和早期治疗试验，以针对 TDP-43 病理生理学的各个方面进行治疗。Irwin 等人在症状前和症状性 C9orf72 突变携带者的脑脊液中检测到 HDGFL2-CE 的事实支持了这一观点 [8]。尽管本文讨论的研究显示 HDGFL2 在 TDP-43 功能障碍时发生错误剪接 [7,8,9]，但 HDGFL2 剪接可能受到其他蛋白质的调节，这可能会混淆其作为 TDP-43 病理和功能障碍标志物的使用。因此，尽管死后组织中的病理性 TDP-43 和 HDGFL2-CE 之间具有很强的相关性，支持其作为 TDP-43 标志物的实用性 [9]，但将 HDGFL2-CE 与一组其他隐性肽（包括 MYO18A、AGRN 和 CAMK2B）偶联值得考虑 [7]，因为它可以提高我们准确检测 TDP-43 功能障碍的信心。因此，值得注意的是，核酸连锁免疫夹心测定（NULISA）等检测方法允许同时测量多个隐性肽 [10]。在这些努力的同时，用于识别 TDP-43 病理个体的替代生物标志物正在出现。

随着该领域进一步探索隐蔽肽在 FTD 和 ALS 中的影响，应考虑研究其他 TDP-43 蛋白病中的 TDP-43 功能障碍。例如，包涵体肌炎患者的肌肉活检显示 TDP-43 聚集体、核 TDP-43 清除率以及 mRNA 转录本（包括 HDGFL2）中包含 CE [11]。最近的工作还确定了 TDP-43 介导的错剪接隐转录本，例如 AD 和 LATE 中的 STMN2、UNC13A 和 HDGFL2 [9,12,13,14]，这表明作为 TDP-43 功能障碍标志物的隐匿肽不仅与 ALS、FTD、AD 和 LATE 相关，还与其他具有混合病症的神经退行性疾病相关，例如路易体痴呆、慢性创伤性脑病、和其他与 AD 相关的痴呆症。

随着我们进一步研究 HDGLF2-CE 作为生物标志物的效用，应阐明 HDGFL2-CE 和其他隐蔽蛋白的功能。Seddighi 等人发现 HDGFL2-CE 改变了 HDGFL2 相互作用组，HDGFL2-CE 与 RNA 结合蛋白的相互作用增加，与细胞骨架蛋白的相互作用减少，这表明 HDGFL2-CE 诱导毒性增加和功能丧失，因此可能影响疾病的发生和进展 [7]。破译转录本中隐蔽外显子包涵体导致神经退行性的病理机制将拓宽我们对疾病发病机制的理解，并可能为治疗 TDP-43 蛋白病提供更有针对性的方法。

不適用。

广告：: 阿尔茨海默病
肌萎缩侧索硬化症（ALS: 肌萎缩侧索硬化症
CE：: 隐蔽外显子
中枢神经系统（CNS）：: 中枢神经系统
脑脊液：: 脑脊液
FTD （FTD）：: 额颞叶痴呆
FTLD 的：: 额颞叶变性
HDGFL2：: 肝癌衍生的生长因子
iPSC：: 诱导多能干细胞
晚：: 边缘系统为主的年龄相关性 TDP-43 脑病
MYO18A 的：: 肌球蛋白 XVIIIA
努丽莎：: 核酸连锁免疫夹心测定
TDP-43：: 43 kDa 的 TAR DNA 结合蛋白

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下载参考资料

作者得到了 Target ALS 基金会（Y.-J.Z.）、美国国立卫生研究院/国家老龄化研究所 [（R01AG085307： Y.-J.Z.）;（P30AG062677：T.F.G.）;和（U19AG063911：T.F.G.）]，美国国立卫生研究院/国家神经疾病和中风研究所 [（P01NS084974：Y.-J.Z 和 T.F.G.）;（R01NS117461：Y.-J.Z. 和 T.F.G.）;（R01 NS121125：T.F.G.）;和（R21NS127331： Y.-J.Z.）]。

作者和单位

美国佛罗里达州杰克逊维尔梅奥诊所神经科学系

Ellen A. Albagli， Anna Calliari， Tania F. Gendron & Yong-Jie Zhang
美国明尼苏达州罗切斯特市梅奥临床医学院梅奥医学院梅奥研究生院疾病神经生物学研究生课程
Tania F. Gendron & Yong-Jie Zhang

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贡献

所有作者都撰写并批准了最终手稿。

通讯作者

与 Tania F. Gendron 或 Yong-Jie Zhang 的通信。

道德批准和参与同意

不適用。

同意发布

作者已审查最终手稿并同意出版。

利益争夺

E.A.A.、A.C.、T.F.G. 和 Y.-J.Z.参与 HDGFL2-CE 的发现和验证，撰写了以前的出版物 [7， 9]。

出版商注

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

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