Protein & CellPub Date : 2025-01-04DOI: 10.1093/procel/pwae037
Zhao Zhang, Hua Jiang, Li Huang, Sixi Liu, Xiaoya Zhou, Yun Cai, Ming Li, Fei Gao, Xiaoting Liang, Kam-Sze Tsang, Guangfu Chen, Chui-Yan Ma, Yuet-Hung Chai, Hongsheng Liu, Chen Yang, Mo Yang, Xiaoling Zhang, Shuo Han, Xin Du, Ling Chen, Wuh-Liang Hwu, Jiacai Zhuo, Qizhou Lian
{"title":"Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: a long-term follow-up pilot study.","authors":"Zhao Zhang, Hua Jiang, Li Huang, Sixi Liu, Xiaoya Zhou, Yun Cai, Ming Li, Fei Gao, Xiaoting Liang, Kam-Sze Tsang, Guangfu Chen, Chui-Yan Ma, Yuet-Hung Chai, Hongsheng Liu, Chen Yang, Mo Yang, Xiaoling Zhang, Shuo Han, Xin Du, Ling Chen, Wuh-Liang Hwu, Jiacai Zhuo, Qizhou Lian","doi":"10.1093/procel/pwae037","DOIUrl":"10.1093/procel/pwae037","url":null,"abstract":"<p><p>Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"16-27"},"PeriodicalIF":13.6,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate aging in mice.","authors":"Sipeng Wu, Yiqi Cai, Lixiao Zhang, Xiang Li, Xu Liu, Guangkeng Zhou, Hongdi Luo, Renjian Li, Yujia Huo, Zhirong Zhang, Siyi Chen, Jinliang Huang, Jiahao Shi, Shanwei Ding, Zhe Sun, Zizhuo Zhou, Pengcheng Wang, Geng Wang","doi":"10.1093/procel/pwae023","DOIUrl":"10.1093/procel/pwae023","url":null,"abstract":"<p><p>One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"28-48"},"PeriodicalIF":13.6,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PDHX acetylation facilitates tumor progression by disrupting PDC assembly and activating lactylation-mediated gene expression.","authors":"Zetan Jiang, Nanchi Xiong, Ronghui Yan, Shi-Ting Li, Haiying Liu, Qiankun Mao, Yuchen Sun, Shengqi Shen, Ling Ye, Ping Gao, Pinggen Zhang, Weidong Jia, Huafeng Zhang","doi":"10.1093/procel/pwae052","DOIUrl":"10.1093/procel/pwae052","url":null,"abstract":"<p><p>Deactivation of the mitochondrial pyruvate dehydrogenase complex (PDC) is important for the metabolic switching of cancer cell from oxidative phosphorylation to aerobic glycolysis. Studies examining PDC activity regulation have mainly focused on the phosphorylation of pyruvate dehydrogenase (E1), leaving other post-translational modifications largely unexplored. Here, we demonstrate that the acetylation of Lys 488 of pyruvate dehydrogenase complex component X (PDHX) commonly occurs in hepatocellular carcinoma, disrupting PDC assembly and contributing to lactate-driven epigenetic control of gene expression. PDHX, an E3-binding protein in the PDC, is acetylated by the p300 at Lys 488, impeding the interaction between PDHX and dihydrolipoyl transacetylase (E2), thereby disrupting PDC assembly to inhibit its activation. PDC disruption results in the conversion of most glucose to lactate, contributing to the aerobic glycolysis and H3K56 lactylation-mediated gene expression, facilitating tumor progression. These findings highlight a previously unrecognized role of PDHX acetylation in regulating PDC assembly and activity, linking PDHX Lys 488 acetylation and histone lactylation during hepatocellular carcinoma progression and providing a potential biomarker and therapeutic target for further development.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"49-63"},"PeriodicalIF":13.6,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"MultiKano: an automatic cell type annotation tool for single-cell multi-omics data based on Kolmogorov-Arnold network and data augmentation.","authors":"Siyu Li, Xinhao Zhuang, Songbo Jia, Songming Tang, Liming Yan, Heyang Hua, Yuhang Jia, Xuelin Zhang, Yan Zhang, Qingzhu Yang, Shengquan Chen","doi":"10.1093/procel/pwae069","DOIUrl":"https://doi.org/10.1093/procel/pwae069","url":null,"abstract":"","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Aberrant outputs of cerebellar nuclei and targeted rescue of social deficits in an autism mouse model.","authors":"Xin-Yu Cai, Xin-Tai Wang, Jing-Wen Guo, Fang-Xiao Xu, Kuang-Yi Ma, Zhao-Xiang Wang, Yue Zhao, Wei Xie, Martijn Schonewille, Chris De Zeeuw, Wei Chen, Ying Shen","doi":"10.1093/procel/pwae040","DOIUrl":"10.1093/procel/pwae040","url":null,"abstract":"<p><p>The cerebellum is heavily connected with other brain regions, sub-serving not only motor but also nonmotor functions. Genetic mutations leading to cerebellar dysfunction are associated with mental diseases, but cerebellar outputs have not been systematically studied in this context. Here, we present three dimensional distributions of 50,168 target neurons of cerebellar nuclei (CN) from wild-type mice and Nlgn3R451C mutant mice, a mouse model for autism. Our results derived from 36 target nuclei show that the projections from CN to thalamus, midbrain and brainstem are differentially affected by Nlgn3R451C mutation. Importantly, Nlgn3R451C mutation altered the innervation power of CN→zona incerta (ZI) pathway, and chemogenetic inhibition of a neuronal subpopulation in the ZI that receives inputs from the CN rescues social defects in Nlgn3R451C mice. Our study highlights potential role of cerebellar outputs in the pathogenesis of autism and provides potential new therapeutic strategy for this disease.</p>","PeriodicalId":20790,"journal":{"name":"Protein & Cell","volume":" ","pages":"872-888"},"PeriodicalIF":13.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11637611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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