AbstractTriosephosphate isomerase deficiency (TPI Df) is a rare multisystem disorder with severe neuromuscular symptoms which arises exclusively from mutations within the TPI1 gene. Studies of TPI Df have been limited due to the absence of mammalian disease models and difficulties obtaining patient samples.

摘要磷酸丙糖异构酶缺乏症（TPI-Df）是一种罕见的多系统疾病，伴有严重的神经肌肉症状，仅由TPI1基因突变引起。由于缺乏哺乳动物疾病模型和难以获得患者样本，TPI-Df的研究受到限制。

Recently, we developed a novel murine model of TPI Df which models the most common disease-causing mutation in humans, TPI1E105D. Using our model in the present study, the underlying pathogenesis of neuromuscular symptoms has been elucidated. This is the first report detailing studies of neuromuscular pathology within a murine model of TPI Df.

最近，我们开发了一种新型的TPI Df小鼠模型，该模型模拟了人类最常见的致病突变TPI1E105D。在本研究中使用我们的模型，已经阐明了神经肌肉症状的潜在发病机理。这是第一份详细介绍TPI Df小鼠模型中神经肌肉病理学研究的报告。

We identified several contributors to neuromuscular symptoms, including neurodegeneration in the brain, alterations in neurotransmission at the neuromuscular junction, and reduced muscle fiber size. TPI Df mice also exhibited signs of cardiac pathology and displayed a deficit in vascular smooth muscle functionality.

我们确定了导致神经肌肉症状的几种因素，包括大脑中的神经变性，神经肌肉接头处神经传递的改变以及肌纤维大小的减小。TPI-Df小鼠还表现出心脏病理学迹象，并表现出血管平滑肌功能缺陷。

Together, these findings provide insight into pathogenesis of the neuromuscular symptoms in TPI Df and can guide the future development of therapeutics..

总之，这些发现提供了对TPI Df中神经肌肉症状发病机理的深入了解，并可以指导治疗学的未来发展。。

IntroductionTriosephosphate isomerase deficiency (TPI Df) is an ultra-rare metabolic disorder that was identified in the 1960’s1. While much has been learned about the disease since its discovery, this knowledge has principally been biochemical. Little is known about pathogenesis of TPI Df within individual organ systems.

引言磷酸丙糖异构酶缺乏症（TPI-Df）是一种极为罕见的代谢紊乱，于1960年被发现1。虽然自发现该疾病以来，人们对其了解很多，但这些知识主要是生物化学的。关于个体器官系统中TPI-Df的发病机理知之甚少。

Human tissue for study is incredibly scarce due to the rarity and severity of the disease, and the age of typical patients. Furthermore, mammalian systems that model the disease well have not existed until recently2. Our newly developed murine model exhibits complex neuromuscular phenotypes akin to phenotypes seen in TPI Df patients and represents an opportunity to learn about the effects of TPI Df on mammals and to elucidate key details of disease pathogenesis2.TPI Df follows an aggressive disease course characterized by hemolytic anemia, neuromuscular dysfunction, and early death.

由于疾病的罕见性和严重性以及典型患者的年龄，用于研究的人体组织非常稀缺。。我们新开发的小鼠模型表现出类似于TPI-Df患者表型的复杂神经肌肉表型，为了解TPI-Df对哺乳动物的影响和阐明疾病发病机制的关键细节提供了机会2.TPI-Df遵循以溶血性贫血，神经肌肉功能障碍和早期死亡为特征的侵袭性疾病过程。

It is important to note that TPI Df can arise from a variety of mutations, though over 80% of cases reported are associated with at least one copy of the TPI1E105D mutation3. The most common disease presentation is homozygosity for the TPI1E105D mutation, responsible for ~ 45% of published TPI Df cases.

重要的是要注意，TPI Df可能由多种突变引起，尽管报告的病例中有80%以上与TPI1E105D突变的至少一个拷贝有关3。。

Despite the variability in genetic presentation, there are some characteristic symptoms that define nearly all genetic presentations of TPI Df. The earliest signs of the disease are anemia, developmental delays, and regressions4,5. Often, patients experience recurrent infections throughout their lifespan, the basis of which is unknown but may be related to the severe anemia patients experience6.

尽管遗传表现存在差异，但仍有一些特征性症状定义了TPI Df的几乎所有遗传表现。该疾病的最早迹象是贫血，发育迟缓和退化4,5。通常，患者在整个生命周期中都会反复感染，其基础尚不清楚，但可能与严重贫血患者的经历有关6。

Neuromuscular dysfunction is widespread among TPI Df patients although its presentation can be variable. Most TPI Df patients will experience hypotonia and dystonia, while some may e.

神经肌肉功能障碍在TPI Df患者中很普遍，尽管其表现可能会有所不同。大多数TPI Df患者会出现肌张力低下和肌张力障碍，而有些患者可能会出现e。

E105D/null animalsTpi1E105D/null animals and their littermates were assessed behaviorally through grip strength and rotarod assays to identify deficits in motor function. Raw grip strength measures were generally lower in Tpi1E105D/null animals when compared to littermate control animals (Fig. 1a and b).

E105D/null动物TPI1E105D/null动物及其同窝仔通过握力和旋转杆测定进行行为评估，以确定运动功能缺陷。与同窝对照动物相比，Tpi1E105D/null动物的原始握力测量值通常较低（图1a和b）。

When grip strength values were normalized to individual body weights, there was no difference in grip strength between Tpi1E105D/null animals and their littermate controls (Fig. 1c and d). A strong deficit was observed in rotarod performance, with Tpi1E105D/null animals falling with an average of 15.58 s from of the start of the assay, whereas littermate control animals had an average latency to fall between 79.21 and 94.63 s (Fig. 1e).

当将握力值标准化为个体体重时，Tpi1E105D/null动物与其同窝对照之间的握力没有差异（图1c和d）。在旋转脚架性能中观察到强烈的缺陷，Tpi1E105D/null动物从测定开始平均下降15.58秒，而同窝对照动物的平均潜伏期在79.21和94.63秒之间（图1e）。

To evaluate when pathology begins to arise, we examined animal body weights over time. Body weights in Tpi1E105D/null animals are not altered in respect to control animals at post-natal day 9 (p9; Fig. 1f and 1g). A slight difference in body weight can be seen in male Tpi1E105D/null animals relative to controls, but not females, at p20 (Fig. 1f and 1g).

为了评估病理学何时开始出现，我们检查了动物体重随时间的变化。Tpi1E105D/null动物的体重在出生后第9天相对于对照动物没有改变（p9；图1f和1g）。在p20时，雄性Tpi1E105D/null动物的体重相对于对照组略有不同，而雌性则没有（图1f和1g）。

A drastic reduction in body weight is evident at days p39-p41 in Tpi1E105D/null animals of both sexes relative to controls (Fig. 1f and g).Figure 1Behavioral phenotype and body weights of Tpi1E105D/null mice. (a and b) Raw four-paw grip strength in male and female animals, respectively. (c and d) Body-weight standardized grip strength in male and female animals, respectively.

相对于对照组，Tpi1E105D/null两性动物在p39-p41天的体重明显下降（图1f和g）。图1 Tpi1E105D/null小鼠的行为表型和体重。（a和b）雄性和雌性动物的原始四爪握力。（c和d）雄性和雌性动物的体重标准化握力。

(e) Latency to fall via Rotarod assay in seconds (s). N = 8 animals per genotype for all assays with 3 within-animal replicates and equal numbers of males and females. Rotarod data was pooled due to absence of sex differences. f and (g) Body-weight trends over development in Tpi1E105D/null animals relative to control.

（e） 通过旋转杆测定法下降的潜伏期（秒）。对于所有测定，每个基因型N=8只动物，动物内重复3次，雄性和雌性数量相等。由于没有性别差异，因此汇总了Rotarod数据。f和（g）相对于对照，Tpi1E105D/无效动物的体重趋势超过发育。

Data availability

数据可用性

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

在当前研究期间生成和/或分析的数据集可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsThis project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. Additional work was completed by the Pitt Histology Core located in the UPMC Children's Hospital of Pittsburgh in the John G.

下载参考文献致谢本项目使用了UPMC希尔曼癌症中心和组织与研究病理学/皮特生物样本核心共享资源，该资源部分由P30CA047904奖项支持。位于约翰·G·匹兹堡UPMC儿童医院的匹兹堡组织学核心完成了额外的工作。

Rangos Sr. Research Center. Echocardiograms were completed through the small-animal ultrasonography core at the University of Pittsburgh and supported by award NIH 1S10OD023684; Advanced High Resolution Rodent Ultrasound Imaging System. We are grateful to Brenda McMahon for conducting echocardiography experiments.

兰戈斯高级研究中心。超声心动图是通过匹兹堡大学的小动物超声检查核心完成的，并得到了NIH 1S10OD023684奖的支持；先进的高分辨率啮齿动物超声成像系统。我们感谢Brenda McMahon进行超声心动图实验。

We gratefully acknowledge grant support for this project via R03 NS119664 (MJP), R01 HD105311 (MJP), R01 HD104346 (MJP), U01 AA020889 (GEH), R35HL 161177 (ACS), T32 GM133332 (TDM), the William C. DeGroat Neuropharmacology fellowship (TDM), and the Save JT Borofka research fund. This work was supported through shared resources within the Pittsburgh Institute for Neurodegenerative Diseases (PIND) and the Department of Pharmacology & Chemical Biology at the University of Pittsburgh.

我们非常感谢通过R03 NS119664（MJP），R01 HD105311（MJP），R01 HD104346（MJP），U01 AA020889（GEH），R35HL 161177（ACS），T32 GM133332（TDM），William C.DeGroat神经药理学奖学金（TDM）和Save JT Borofka研究基金对该项目的资助。这项工作得到了匹兹堡神经退行性疾病研究所（PIND）和匹兹堡大学药理学与化学生物学系的共享资源的支持。

We are thankful to Dr. Dandan Sun and Dr. Tim Greenamyre for the use of microscopy equipment, as well as Dr. Kyle Farmer for assistance with imaging.Author informationAuthors and AffiliationsCenter for Neuroscience at the University of Pittsburgh, Pittsburgh, PA, USATracey D. Myers, Yizhi Li, Paulina Cabada-Aguirre, Gregg E.

我们感谢Dandan Sun博士和Tim Greenamyre博士使用显微镜设备，以及Kyle Farmer博士在成像方面的帮助。作者信息宾夕法尼亚州匹兹堡匹兹堡大学神经科学作者和附属机构，USATraceyD.Myers，Li，PaulinaCabadaAguirre，Gregg E。

Homanics, Stephen D. Meriney & Michael J. PalladinoDepartment of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USATracey D. Myers, Stefanie Taiclet, Paulina Cabada-Aguirre, Emily Kuti, Kaitlin McClure, Marta Wolosowicz, Gregg E. Homanics, Adam C. Straub & Michael J. PalladinoPittsburgh Institute.

Homanics，Stephen D.Meriney和Michael J.PalladinoDepartment of Pharmacology&Chemical Biology，匹兹堡大学，宾夕法尼亚州匹兹堡，USATracey D.Myers，Stefanie Taiclet，Paulina Cabada Aguirre，Emily Kuti，Kaitlin McClure，Marta Wolosowicz，Gregg E.Homanics，Adam C.Straub和Michael J.PalladinoPittsburgh Institute。

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PubMed Google ScholarContributionsT.D.M contributed to the conception, design, data acquisition, data analysis, interpretation of data, and drafting of the manuscript. Y.L., S.T., and P.C.A. contributed to the design, data acquisition, data analysis, interpretation of data, and review of the manuscript.

。D、 M为稿件的概念，设计，数据采集，数据分析，数据解释和起草做出了贡献。Y、 L.，S.T。和P.C.A.为稿件的设计，数据采集，数据分析，数据解释和审查做出了贡献。

E.K., K.M., and C.B. contributed to data analysis and review of the manuscript. M.W. contributed to data acquisition and review of the manuscript. G.E.H. contributed to data acquisition and review of the manuscript. A.C.S. contributed to design, interpretation of data, and review of the manuscript. S.D.M.

E、 K.，K.M。和C.B.为手稿的数据分析和审查做出了贡献。M、 W.为数据采集和稿件审查做出了贡献。G、 E.H.为数据采集和稿件审查做出了贡献。A、 C.S.为设计，解释数据和审查手稿做出了贡献。S、 D.M。

contributed to design, interpretation of data, and review of the manuscript. M.J.P. contributed to the conception, design, interpretation of data, and drafting of the manuscript.Corresponding authorCorrespondence to.

有助于设计，解释数据和审查手稿。M、 J.P.为手稿的概念，设计，数据解释和起草做出了贡献。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleMyers, T.D., Li, Y., Taiclet, S. et al. Neuromuscular dysfunction and pathogenesis in triosephosphate isomerase deficiency.

转载和许可本文引用本文Myers，T.D.，Li，Y.，Taiclet，S。等人。磷酸丙糖异构酶缺乏症的神经肌肉功能障碍和发病机制。

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