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神奇D型肽：阿尔茨海默病治疗新靶点Tau蛋白形成的纤维状聚集体是导致阿尔茨海默病（AD）患者进展的关键因素。Nature杂志发表了一项突破性研究，揭示了D型肽D-TLKIVWC分解tau纤维的全新机制。研究发现D型肽通过形成"模拟淀粉样"纤维，在结合tau纤维时将天然右旋结构变为左旋，随后破坏tau分子间的氢键来实现tau蛋白纤维分解。图片来源：123RF此前研究已发现D-TLKIVWC能在无需额外能量输入的情况下分解AD患者大脑提取的超稳定tau纤维。最新研究则深入解析了这一过程的分子机制。当D型肽自组装成右旋的"模拟淀粉样"纤维后，与左旋的tau纤维结合时会暂时被迫采用左旋构象。这种被迫扭曲产生的应变在D型肽恢复其天然右旋状态时释放，形成强大的分子水平扭矩，直接破坏tau蛋白间的连接。该机制不仅解释了D型肽分解tau纤维的能量来源，还发现类似的应变释放原理可能普遍存在于其他淀粉样纤维的分解过程中。这一发现为开发靶向蛋白聚集体的首创新药提供了重要理论基础，有望推动阿尔茨海默病等神经退行性疾病的治疗策略革新。论文标题：How short peptides disassemble tau fibrils in Alzheimer's diseaseDOI: 10.1038/s41586-025-09244-z脊髓损伤治疗新策略脊髓损伤（SCI）后患者常面临严重的运动功能障碍。近日，一项发表于Science Translational Medicine的研究为不完全性脊髓损伤的治疗带来了新希望。研究者发现，通过抑制组蛋白去乙酰化酶3（HDAC3）可以促进神经突生长，并利用纳米颗粒递送技术显著提升了治疗效果。研究团队首先筛选了表观遗传调控因子，结果显示敲除HDAC3能够促进小鼠脊髓神经元的神经突生长。为了增强体内效果，他们开发了一种新型神经营养纳米颗粒平台（oGHDAC3），该平台由明胶甲基丙烯酰微球与优化的狂犬病糖蛋白衍生肽结合而成。在脊髓损伤小鼠模型中，oGHDAC3或腺相关病毒介导的神经元HDAC3缺失促进了脊髓-腰段绕行回路的形成，显著改善了运动功能。这项研究不仅揭示了HDAC3抑制促进脊髓损伤后运动功能恢复的机制，还开发了一种可转化的纳米递送平台，为不完全性脊髓损伤的治疗提供了新思路。未来，这种结合表观遗传调控和纳米技术的策略有望为脊髓损伤患者带来更有效的治疗方案。论文标题：Neuronal HDAC3 knockdown promotes propriospinal detour pathway formation and locomotor recovery in a mouse model of spinal cord injuryDOI: 10.1126/scitranslmed.adp1873研究发现辅酶Q10合成新途径辅酶Q10是人体内重要的脂溶性抗氧化剂，其水平降低不仅会导致罕见的原发性辅酶Q10缺乏症，还与常见的神经退行性疾病和衰老过程密切相关。然而，直接补充辅酶Q10并不能有效提高其在脑组织中的含量。最新发表于Nature的研究发现，哺乳动物体内存在一条全新的辅酶Q10头部基团合成通路，其中4-羟基苯丙酮酸双加氧酶样蛋白（HPDL）通过产生4-羟基扁桃酸（4-HMA）来合成辅酶Q10头部基团前体4-羟基苯甲酸（4-HB）。研究人员发现，给Hpdl基因敲除小鼠补充4-HMA或4-HB后，这些前体物质成功被整合到脑组织中的辅酶Q9和辅酶Q10分子中。口服这两种化合物可使超过90%的基因缺陷小鼠存活至成年。此外，4-HB治疗还显著改善了一名因HPDL基因突变导致进行性痉挛患者的神经症状。这项研究不仅揭示了辅酶Q10头部基团中间产物在体内重建辅酶Q10合成的潜力，更为由HPDL变异导致的线粒体脑病提供了全新的治疗思路。论文标题：Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathyDOI: 10.1038/s41586-025-09246-x调节性T细胞可逆转心肌纤维化肥厚型心肌病（HCM）是一种常见且严重的遗传性心肌疾病，尽管科学家已基本明确肌节蛋白基因突变如何破坏心肌细胞功能，但涉及非心肌细胞的病理机制仍不清楚。最新发表在Science Translational Medicine的研究发现，人类HCM患者的心脏中存在慢性白细胞浸润和免疫细胞异常激活现象，且这种免疫反应在疾病中晚期尤为显著。 图片来源：123RF借助模拟人类HCM病理特征的小鼠模型，研究发现当清除淋巴细胞时，小鼠心脏纤维化和功能恶化会显著加剧。进一步分析显示，HCM心脏中的调节性T细胞（Treg细胞）会随时间增加，但其免疫抑制功能发生改变。 而将脾脏Treg细胞移植到患病小鼠体内后，心脏纤维化明显减轻，心功能得到改善；低剂量IL-2/抗IL-2复合物通过特异性扩增Treg细胞，同样能减少心脏纤维化和巨噬细胞浸润。 这些发现不仅揭示了免疫系统在HCM进展中的关键作用，更为临床开发靶向Treg细胞的抗纤维化疗法提供了直接依据。论文标题：Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathyDOI: 10.1126/scitranslmed.adq3516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：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。更多推荐点个“在看”再走吧~

NEW YORK, July 9, 2025 /PRNewswire/ -- The value of a recent biochemical discovery can be seen in the case of an 8-year-old boy, who was playing typical sports in August 2023, but by November needed a wheelchair because of a rare disease that caused worsening paralysis. As part of a new study, neurologists at NYU Langone Health treated the boy with an experimental compound that partially reversed his rapid decline. Two months after beginning treatment, he was able to walk long distances again and even run. Published online July 9 in the journal Nature, the work revolves around mitochondria, the "powerhouses" of human cells where sugars and fats are "burned" to produce energy. This energy production requires coenzyme Q10 (CoQ10), which is made by human cells. The boy described in the paper was born with a potentially fatal condition called HPDL deficiency that hinders the building of CoQ10, one of several mitochondrial diseases that affect thousands nationally and come with paralysis, limb stiffness, and fatigue. The child's experimental treatment was made possible in part by a 2021 study led by Robert Banh, PhD, who was a postdoctoral fellow at the time in the lab of Michael E. Pacold, MD, PhD, assistant professor in the Department of Radiation Oncology at NYU Grossman School of Medicine and its Perlmutter Cancer Center. NYU Langone Health's deeply integrated system enabled researchers to convert their lab work into an effective, experimental treatment. Banh's original work revealed that CoQ10 building in mitochondria starts when HPDL (the enzyme hydroxyphenylpyruvate dioxygenase-like) turns a compound called 4-hydroxymandelate (4-HMA) into another called 4-hydroxybenzoate (4-HB). Cells then use 4-HB to build a part of CoQ10 necessary for energy production. Based on this discovery, the Pacold lab was able to show that both 4-HMA or 4-HB can be used to restore CoQ10 synthesis and counter related brain damage in mice engineered to lack HPDL. Led by Guangbin Shi, a senior research assistant in Pacold's lab, the researchers found that adding 4-HMA or 4-HB to these animals' water enabled more than 90% of them to move near normally and live to adulthood, instead of becoming paralyzed and dying. When the researchers were approached by the parents of the fast-declining child with HPDL deficiency, they shared their evidence with NYU Langone pediatric neurologists Claire Miller, MD, PhD, and Giulietta Riboldi, MD, PhD. The two clinicians then worked with a team of experts to secure government authorization to treat the boy with 4-HB. In a stunning result, the treatment partially countered the child's worsening spasticity, a combination of stiffness and paralysis, in less than two months. "To our knowledge, this is the first demonstration that neurological symptoms of a primary CoQ10 deficiency can be stabilized or improved by supplying, not CoQ10 itself, but instead its smaller, more easily processed precursors, which cells then use to build more of the coenzyme," said Pacold, senior author of the new study in Nature. Beyond rare diseases, cellular supplies of CoQ10 are known to drop as people develop heart disease, diabetes, and Alzheimer's disease, and in all of us as we age. For these reasons, the industry supplying CoQ10 as a dietary supplement is expected to represent a billion-dollar market within a decade. The problem, say the current study authors, is that, even at high doses, less than 5 percent of ingested CoQ10 makes it into the body because of its structure and size. This may explain why CoQ10 has failed to reverse the neurological symptoms of HPDL/CoQ10 deficiencies, the researchers say. Recovery Window For the current study, the Pacold lab acquired mice engineered to lack HPDL function, which were known to quickly become paralyzed. The team also found that these mice had smaller-than-normal mitochondria, as well as a smaller cerebellum and malfunctioning Purkinje cells, both of which control movement. Remarkably, replacement therapy with 4-HMA partially reversed the abnormalities by encouraging the building of the mouse version of CoQ10. Then in 2023, with the mouse results in hand, Pacold met the parents, both of whom had genetic mutations that sabotaged HPDL function and caused two of their children to die in infancy. Their other child had thrived for 8 years but had recently declined. A team quickly assembled to include Drs. Miller and Riboldi, members of NYU Langone's Office of Science & Research, Regulatory Affairs, Technology Opportunities & Ventures, the Office of General Counsel, and the Conflicts of Interest Management Unit (CIMU), and gained NYU Langone approval under its policies to clinically test 4-HB. The team next gained approval from the U.S. Federal Drug Administration for the boy's experimental treatment under a process called expanded access. It enables physicians caring for a patient with a life-threatening disease to use an experimental treatment when no other options are available. With subsequent approval from NYU Langone's Institutional Review Board, the patient's treatment started in December 2023. Treated daily with the experimental compound dissolved in water, the patient saw improved balance and endurance over the following weeks. Just before the patient departed from NYU Langone two months into the trial (to continue it at home), Miller says, the boy went for one-and-a-half mile walk with his family in Central Park. The recovery, however, was partial, with some spasticity and gait issues remaining. The discovery of the experimental treatment was serendipitous, occurring while the Pacold Lab was investigating the anti-cancer potential of targeting CoQ10 production. During that test, the team happened to discover that the CoQ10 precursors caused recovery from neurodegenerative processes in one of its animal models. This ultimately led to an effort across NYU Langone to design the child's treatment. Further, children with HPDL deficiencies are known to have a range of disease severity depending on their specific versions of key variant genes, from no function (fatal) to levels of partial function. The clinical and research teams theorize that the treated child still had some HPDL function and so was able to develop normally until a certain stage. The team's mouse data suggest that there is a time window in neural development during which the effects of HPDL deficiency will be most reversible with CoQ10 precursor treatment, and after which treatment will have little effect. Identifying this window, along with the most effective dose, in larger studies will be the focus of the next round of research. NYU Langone owns the intellectual property developed in the Pacold lab and covering the treatment outlined above, which NYU Langone and Dr. Pacold are seeking to license to a partner to develop CoQ10 intermediates. Dr. Pacold in April received the Pershing Square Foundation's "MIND" Prize , which came with $750,000 to support this work. Along with Pacold, Banh, Shi, Riboldi, and Miller, NYU Langone study authors included Sota Kuno, Quentin Spillier, Zixuan Wang, and Drew Jones from the Department of Radiation Oncology, Megan Korn and Wyatt Tran from the Department of Biochemistry, Lia Ficaro in the Metabolomics Core Research Laboratory, Begoña Gamallo-Lana and Adam Mar of the Rodent Behavioral Laboratory, Matija Snuderl in the Department of Pathology, and Soomin Song in the IonLab. Banh had been a post-doc in the labs of Dr. Pacold, and of Alec C. Kimmelman, MD, PhD, director of the Perlmutter Cancer Center, before joining the faculty as an assistant professor in the Department of Biochemistry and Molecular Pharmacology. Dr. Kimmelman was recently named Dean of the NYU Grossman School of Medicine and chief executive officer of NYU Langone Health. "Research breakthroughs show their true impact when they change a family's life," Dr. Kimmelman said. "Thanks to an extraordinary team working across our integrated system, we were able to safely and effectively get this treatment from a bench in the lab to a patient in need." Authors at other institutions were Alejandro Rey Hipolito, Tao Lin, and Roy Sillitoe in the departments of Pathology and Immunology at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital; as well as Salsabiel El Nagar and Alexandra Joyner in the Developmental Biology Program at Memorial Sloan Kettering Cancer Center. The research was supported by National Institutes of Health grants NIGMS R35 MIRA 1R35GM147119, and NCI R37CA289040, Perlmutter Cancer Center grant P30CA016087, a Damon Runyon-Rachleff Innovation Award, and Dale Frey Breakthrough awards DRR 63-20 and DRG-50-22, Tara Miller Melanoma Foundation / MRA Young Investigator Award 668365, and American Cancer Society Research Scholar Award RSG-21-115-01-MM. Additional funding came from the Harry J. Lloyd Charitable Trust, an Irma T. Hirschl Career Scientist Award, a Concern Foundation Conquer Cancer Now Grant, and from NYU Langone Health Technology Opportunities and Ventures. The clinical portion of the research was supported by an NYU CTSA grant (includes UL1 TR001445, KL2 TR001446, and TL1 TR001447) and by funding provided through a Pershing Square-Sohn Cancer Prize from the Pershing Square Foundation. Pacold, Banh, Shi, and Spillier are co-inventors on patents related to the use of 4-HMA, 4-HB, and analogues in the diagnosis and treatment of neurodevelopmental and other diseases assigned to New York University. The treatment was conducted and supervised by Miller and Riboldi under an institutional conflict-of-interest management plan implemented by NYU Langone Health in accordance with its policies. Pacold consulted on the clinical protocol, while Miller and Riboldi directed the course of treatment in accordance with the plan. About NYU Langone Health NYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone No. 1 out of 115 comprehensive academic medical centers across the nation for three years in a row, and U.S. News & World Report recently placed nine of its clinical specialties among the top five in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise. Media Inquiries: Shira Polan (through July 13 only) Phone: 212-404-4279 [email protected] Greg Williams Phone: 212-404-3500 [email protected] SOURCE NYU Grossman School of Medicine and NYU Langone Health WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED