Biochemical Journal最新文献

Leucine-rich repeat kinase 2 biomarkers for Parkinson's disease. 富含亮氨酸重复激酶2的帕金森病生物标志物。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-28 DOI: 10.1042/BCJ20253099

Nicolas Dzamko

引用次数: 0

LRRK2-mediated mitochondrial dysfunction in Parkinson's disease. lrrk2介导的帕金森病线粒体功能障碍。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-28 DOI: 10.1042/BCJ20253062

Silas A Buck, Laurie H Sanders

{"title":"LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.","authors":"Silas A Buck, Laurie H Sanders","doi":"10.1042/BCJ20253062","DOIUrl":"https://doi.org/10.1042/BCJ20253062","url":null,"abstract":"Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, rigidity, and bradykinesia as well as degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). A minority of PD cases are familial and are caused by a single genetic mutation. One of the most common PD-causing genes is leucine-rich repeat kinase 2 (LRRK2), which causes an autosomal dominant PD that presents very similarly to sporadic PD. Pathogenic mutations in LRRK2 increase its kinase activity, indicated by both LRRK2 autophosphorylation and phosphorylation of its substrates. To date, the mechanism(s) by which elevated LRRK2 kinase activity induces DA neuron degeneration and PD has not been fully elucidated. One potential mechanism may involve the role of LRRK2 on mitochondria, as mitochondrial dysfunction has been linked to PD pathogenesis, and exciting recent evidence has connected PD pathogenic mutations in LRRK2 to multiple aspects of mitochondrial dysfunction associated with the disease. In this review, we discuss the current knowledge implicating LRRK2 in mitochondrial energetics, oxidative stress, genome integrity, fission/fusion, mitophagy, and ion/protein transport in PD, as well as examine the potential role LRRK2 may play in mediating the effects of mitochondrial therapeutics being investigated for treatment of PD.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular basis and therapeutic implications of binary YAPOn/YAPOff cancer classes. YAPOn/YAPOff二元肿瘤的分子基础及其治疗意义。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-28 DOI: 10.1042/BCJ20253077

Pinky Sharma, Yale S Michaels, Joel D Pearson

{"title":"Molecular basis and therapeutic implications of binary YAPOn/YAPOff cancer classes.","authors":"Pinky Sharma, Yale S Michaels, Joel D Pearson","doi":"10.1042/BCJ20253077","DOIUrl":"https://doi.org/10.1042/BCJ20253077","url":null,"abstract":"Cancers have traditionally been classified based on their tissue of origin. However, with advances in sophisticated genome sequencing techniques and progression toward an era of precision medicine, it has become increasingly clear that classifying tumors based on unifying molecular features instead of tissue of origin may hold the key to improving patient outcomes. Various efforts have been undertaken to address this critical aspect of cancer biology, but it is still unclear as to the best approach to stratify tumors into different molecular classes. One approach is to define many small subclasses based on complex molecular signatures, while another option is to divide cancers into larger groups based on higher-order features of cancer behavior. This latter approach holds appeal as it may provide opportunities to identify broadly relevant therapeutics. However, our understanding of these fundamental 'rules' of cancer biology and how they can be used to better classify and treat cancers is in its infancy. We recently demonstrated that cancers can be functionally stratified into binary YAPon and YAPoff super-classes with unique therapeutic vulnerabilities based on distinct expression and function of the transcriptional coactivators, YAP and TAZ. In YAPon cancers, YAP and TAZ drive oncogenesis, whereas in YAPoff cancers, YAP and TAZ are instead tumor suppressors. In this review, we discuss our understanding of these distinct cancer classes with a focus on the mechanisms that underlie the opposite function of YAP/TAZ in YAPon and YAPoff cancers, as well as the potential therapeutic implications of these findings.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 11","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The bacterial transcription terminator, Rho, functions as an RNA:DNA hybrid (RDH) helicase in vivo. 细菌转录终止子Rho在体内起RNA:DNA杂交解旋酶的作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-26 DOI: 10.1042/bcj20253089

Ankita Bhosale,Ranjan Sen

{"title":"The bacterial transcription terminator, Rho, functions as an RNA:DNA hybrid (RDH) helicase in vivo.","authors":"Ankita Bhosale,Ranjan Sen","doi":"10.1042/bcj20253089","DOIUrl":"https://doi.org/10.1042/bcj20253089","url":null,"abstract":"Ribonuclease HI (rnhA) removes the deleterious RNA:DNA hybrids (RDHs) by cleaving its RNA component. The bacterial transcription terminator Rho is an RNA-dependent 5' → 3' helicase capable of unwinding RDH formed on a single-stranded RNA in vitro. We hypothesize that Rho might be directly involved in RDH removal in vivo. Here, we demonstrate that Rho primary RNA-binding site (PBS) mutants defective in RNA binding and helicase activity are synthetically lethal specifically when RNase HI is absent. This lethality was not observed in the absence of RNase HII (rnhB) alone. Rho-PBS mutants in an rnhA- strain exhibited increased plasmid-concatemer and plasmid copy number, altered cell morphology, and were highly susceptible to DNA-damaging agents. These Rho mutants increased the accumulation of RDHs in vivo, suggesting defects in the RDH removal process. Rho was colocalized to RDHs in vivo when RNase HI was absent. Certain catalytically inactive mutants of RNase H that bind to the RDH blocked the entry of Rho to the RDH, inducing cell death, indicating the role of Rho in the removal of deleterious RDHs in the absence of RNase HI. Under in vitro conditions, Rho was capable of binding to the RDHs and unwinding them in a rut-site-dependent manner. Therefore, we concluded that in the absence of RNase HI, Rho, by its RNA-dependent helicase activity, is capable of unwinding RDHs in a rut-site-dependent manner. These results establish the non-transcription terminator role of Rho and its functional synergy with RNase HI in vivo.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"16 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reconstituted systems for studying the architecture and dynamics of actin networks. 用于研究肌动蛋白网络结构和动态的重构系统。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-23 DOI: 10.1042/bcj20253044

Alice Cantat,Alexandra Colin

{"title":"Reconstituted systems for studying the architecture and dynamics of actin networks.","authors":"Alice Cantat,Alexandra Colin","doi":"10.1042/bcj20253044","DOIUrl":"https://doi.org/10.1042/bcj20253044","url":null,"abstract":"Actin, a ubiquitous protein essential for numerous cellular functions, is found in all eukaryotes. Despite extensive research across molecular to organismal scales, fundamental questions persist regarding the regulation of dynamic actin architectures, their interaction with membranes, and their mechanical properties. Characterizing the factors governing these processes presents significant challenges. This review emphasizes the value of simplified, reconstituted systems in addressing these unresolved questions. We particularly highlight the critical importance of macroscopic, network-level reconstitutions for tackling these issues. We first describe the available methodological toolkit for (1) controlling actin polymerization spatiotemporally and (2) confining actin networks within closed environments to examine boundary constraint effects or the impact of limited component availability on network properties. We then review studies employing these reconstituted systems to investigate how actin architecture influences various processes and how dynamic actin structures are established and maintained. Further, we discuss how network-level reconstitutions have enhanced our understanding of actin networks' mechanical properties and their interaction with the lipid membranes. Throughout the review, we discuss future perspectives for each topic and explain how macroscale reconstitutions can provide deeper mechanistic insights into actin-related processes.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"23 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in vitro. 多胺化与亚精胺增强致病性tau构象，同时减少丝状聚集体的形成。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-22 DOI: 10.1042/bcj20253079

Mohammed Alhadidy,Rebecca Mueller,Jared Lamp,Nicholas Kanaan

{"title":"Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in vitro.","authors":"Mohammed Alhadidy,Rebecca Mueller,Jared Lamp,Nicholas Kanaan","doi":"10.1042/bcj20253079","DOIUrl":"https://doi.org/10.1042/bcj20253079","url":null,"abstract":"Tau is subject to a broad range of post-translational modifications (PTMs) that regulate its biological activity in health and disease, including microtubule (MT) dynamics, aggregation, and adoption of pathogenic conformations. The most studied PTMs of tau are phosphorylation and acetylation; however, the salience of other PTMs is not fully explored. Tissue transglutaminase (TG) is an enzyme whose activity is elevated in Alzheimer's disease (AD). TG action on tau may lead to intramolecular and intermolecular cross-linking along with the incorporation of cationic polyamines [e.g. spermidine (SPD)] onto glutamine residues (Q). Even though SPD levels are significantly elevated in AD, the effects of SPD polyamination on tau biology have yet to be examined. In this work, we describe a method to produce recombinant SPD-modified tau where SPD modifications are mainly localized to Q residues within the N-terminus. MT binding and polymerization assays showed that SPD modification does not significantly alter tau's binding to MTs but increases MT polymerization kinetics. In addition, biochemical and biophysical assays showed that SPD polyamination of tau markedly reduces tau polymerization into filamentous and β-sheet containing aggregates. On the other hand, SPD modification promotes the formation of pathogenic conformations (e.g. oligomerization and misfolding) by tau with or without inducing tau polymerization. Taken together, these data suggest that SPD polyamination of tau enhances its ability to polymerize microtubules and favors the adoption of pathogenic tau conformations but not filamentous aggregates in vitro.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"31 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cas11 augments Cascade functions in type I-E CRISPR system but is redundant for gene silencing and plasmid interference. Cas11增强了I-E型CRISPR系统中的Cascade功能，但在基因沉默和质粒干扰中是多余的。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-22 DOI: 10.1042/bcj20253056

Neha Pandey,Chitra Misra,Devashish Rath

{"title":"Cas11 augments Cascade functions in type I-E CRISPR system but is redundant for gene silencing and plasmid interference.","authors":"Neha Pandey,Chitra Misra,Devashish Rath","doi":"10.1042/bcj20253056","DOIUrl":"https://doi.org/10.1042/bcj20253056","url":null,"abstract":"The structural and mechanistic complexity of Escherichia coli's type I CRISPR-Cas system compared to the multidomain, single effector protein-based type II systems, limits its application in genome editing and silencing. Despite higher prevalence of the type I endogenous systems in bacteria, significant research has focused on improving the type II systems. While the type-I CRISPR system possesses several advantages over others, it may benefit from further studies to simplify the system for ease of use. To enable this, the dispensability of the type-I Cascade components (Cas8, Cas11, Cas7, Cas5, Cas6) for genome editing and silencing applications was evaluated in vivo. We created deletion variants of each of the Cascade components and investigated their effects on gene silencing and plasmid interference in two genetically distinct Escherichia coli lineages, BW25113, a K-12 strain that bears an endogenous, albeit repressed type I-E CRISPR system and BL21, a natural mutant lacking the type I-E CRISPR-Cascade system. Cas8, Cas7 and Cas5 were found to be indispensable for gene silencing and plasmid interference. Dispensability of Cas6, which is involved in crRNA maturation, was strain-dependent. Notably, Cas11 which has no definitive function assigned to it, was found to be dispensable for gene silencing and plasmid interference.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"14 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Excess Wnt in neurological disease. 神经疾病中过量的Wnt。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-16 DOI: 10.1042/BCJ20240265

Danielle M Pascual, Delaram Jebreili Rizi, Harsimran Kaur, Paul C Marcogliese

引用次数: 0

Multifaceted roles of Epac signaling in renal functions. Epac信号在肾功能中的多重作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-14 DOI: 10.1042/bcj20253103

Oleh Pochynyuk,Kyrylo Pyrshev,Xiaodong Cheng

引用次数: 0

GPCR signaling via cAMP nanodomains. 通过cAMP纳米结构域的GPCR信号传导。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-13 DOI: 10.1042/BCJ20253088

Rahul Yadav, Manuela Zaccolo

{"title":"GPCR signaling via cAMP nanodomains.","authors":"Rahul Yadav, Manuela Zaccolo","doi":"10.1042/BCJ20253088","DOIUrl":"10.1042/BCJ20253088","url":null,"abstract":"G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, mediating essential physiological responses through diverse intracellular signaling pathways. When coupled to Gs or Gi proteins, GPCR modulates the synthesis of 3'-5'-cyclic adenosine monophosphate (cAMP), which governs a wide array of processes, ranging from cellular growth and survival to metabolic regulation. Studies have highlighted that cAMP is not uniformly distributed within cells but instead is compartmentalized into highly localized nanodomains. These nanodomains, mostly regulated by phosphodiesterases (PDEs), play a critical role in enabling signal precision and functional effects that are specific to individual stimuli. GPCRs can initiate distinct cAMP responses based on their localization within the cell, with evidence showing that both receptors resident at the plasma membrane and intracellular receptors-including endosomal, Golgi, and nuclear GPCRs-elicit unique cAMP signaling profiles. This review examines the mechanisms underlying GPCR signaling through cAMP nanodomains. We focus on the role of PDE-mediated cAMP degradation in shaping local cAMP signals, the emerging views on mechanisms that may contribute to signal compartmentalization, and the role of intracellular membrane compartments. By exploring these aspects, we aim to highlight the complexity of GPCR signaling networks and illustrate some of the implications for the regulation of cellular function.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 10","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0