Nature Structural & Molecular Biology最新文献

{"title":"African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1","authors":"Pilar Álvarez Jerez, Peter Wild Crea, Daniel M. Ramos, Emil K. Gustavsson, Mandy Radefeldt, Andrey Damianov, Mary B. Makarious, Oluwadamilola O. Ojo, Kimberley J. Billingsley, Laksh Malik, Kensuke Daida, Sarah Bromberek, Fangle Hu, Zachary Schneider, Aditya L. Surapaneni, Julia Stadler, Mie Rizig, Huw R. Morris, Caroline B. Pantazis, Hampton L. Leonard, Laurel Screven, Yue A. Qi, Mike A. Nalls, Sara Bandres-Ciga, John Hardy, Henry Houlden, Celeste Eng, Esteban González Burchard, Linda Kachuri, Chia-Ho Lin, Douglas L. Black, Global Parkinson’s Genetics Program (GP2), Andrew B. Singleton, Steffen Fischer, Peter Bauer, Xylena Reed, Mina Ryten, Christian Beetz, Michael Ward, Njideka U. Okubadejo, Cornelis Blauwendraat","doi":"10.1038/s41594-024-01423-2","DOIUrl":"10.1038/s41594-024-01423-2","url":null,"abstract":"Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations. GBA1 is a gene of high clinical and therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher disease and monoallelic variants confer risk for PD and dementia with Lewy bodies, likely by reducing the function of glucocerebrosidase. Interestingly, the African ancestry-specific GBA1 risk variant is a noncoding variant, suggesting a different mechanism of action. Using full-length RNA transcript sequencing, we identified partial intron 8 expression in risk variant carriers (G) but not in nonvariant carriers (T). Antibodies targeting the N terminus of glucocerebrosidase showed that this intron-retained isoform is likely not protein coding and subsequent proteomics did not identify a shorter protein isoform, suggesting that the disease mechanism is RNA based. Clustered regularly interspaced short palindromic repeats editing of the reported index variant ( rs3115534 ) revealed that this is the sequence alteration responsible for driving the production of these transcripts containing intron 8. Follow-up analysis of this variant showed that it is in a key intronic branchpoint sequence and, therefore, has important implications in splicing and disease. In addition, when measuring glucocerebrosidase activity, we identified a dose-dependent reduction in risk variant carriers. Overall, we report the functional effect of a GBA1 noncoding risk variant, which acts by interfering with the splicing of functional GBA1 transcripts, resulting in reduced protein levels and reduced glucocerebrosidase activity. This understanding reveals a potential therapeutic target in an underserved and underrepresented population. Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1955-1963"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01423-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811350","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}

{"title":"30 years of structural and molecular biology and counting","authors":"","doi":"10.1038/s41594-024-01459-4","DOIUrl":"10.1038/s41594-024-01459-4","url":null,"abstract":"As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1811-1811"},"PeriodicalIF":12.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41594-024-01459-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811391","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}

{"title":"Supporting structural biologists in Africa requires resources and capacity building","authors":"Emmanuel Nji, Aurélien F. A. Moumbock, Katharina C. Cramer, Nicolas V. Rüffin, Jamaine Davis, Oluwatoyin A. Asojo, Julia J. Griese, Amma A. Larbi, Michel N. Fodje","doi":"10.1038/s41594-024-01438-9","DOIUrl":"10.1038/s41594-024-01438-9","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1814-1815"},"PeriodicalIF":12.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753750","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":"Looking back at the timely launch of Nature Structural Biology in 1994","authors":"Christian Cambillau","doi":"10.1038/s41594-024-01436-x","DOIUrl":"10.1038/s41594-024-01436-x","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1812-1812"},"PeriodicalIF":12.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751089","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":"Keeping in touch with the road not taken","authors":"Javier Apfeld","doi":"10.1038/s41594-024-01443-y","DOIUrl":"10.1038/s41594-024-01443-y","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1816-1817"},"PeriodicalIF":12.5,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751076","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":"Diverse anti-NMDAR autoantibodies from individuals with encephalitis","authors":"Zoe Jamet, Frederic Villega, Laurent Groc","doi":"10.1038/s41594-024-01435-y","DOIUrl":"10.1038/s41594-024-01435-y","url":null,"abstract":"Autoantibodies targeting glutamatergic N-methyl-d-aspartic acid receptors (NMDARs) are found in people with anti-NMDAR encephalitis. Two studies reveal that patient-derived autoantibodies are diverse in their epitope binding and modes of action on the NMDAR, providing insights into the mechanisms behind autoantibody-induced NMDAR hypofunction.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1821-1823"},"PeriodicalIF":12.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718940","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":"A lesson in symmetry","authors":"Magdalena Boncler","doi":"10.1038/s41594-024-01437-w","DOIUrl":"10.1038/s41594-024-01437-w","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1813-1813"},"PeriodicalIF":12.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718784","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":"Evolution and function of chromatin domains across the tree of life","authors":"Michael-Florian Szalay, Blanka Majchrzycka, Ivana Jerković, Giacomo Cavalli, Daniel M. Ibrahim","doi":"10.1038/s41594-024-01427-y","DOIUrl":"10.1038/s41594-024-01427-y","url":null,"abstract":"The genome of all organisms is spatially organized to function efficiently. The advent of genome-wide chromatin conformation capture (Hi-C) methods has revolutionized our ability to probe the three-dimensional (3D) organization of genomes across diverse species. In this Review, we compare 3D chromatin folding from bacteria and archaea to that in mammals and plants, focusing on topology at the level of gene regulatory domains. In doing so, we consider systematic similarities and differences that hint at the origin and evolution of spatial chromatin folding and its relation to gene activity. We discuss the universality of spatial chromatin domains in all kingdoms, each encompassing one to several genes. We also highlight differences between organisms and suggest that similar features in Hi-C matrices do not necessarily reflect the same biological process or function. Furthermore, we discuss the evolution of domain boundaries and boundary-forming proteins, which indicates that structural maintenance of chromosome (SMC) proteins and the transcription machinery are the ancestral sculptors of the genome. Architectural proteins such as CTCF serve as clade-specific determinants of genome organization. Finally, studies in many non-model organisms show that, despite the ancient origin of 3D chromatin folding and its intricate link to gene activity, evolution tolerates substantial changes in genome organization. Szalay et al. discuss cross-kingdom similarities and differences in 3D chromatin folding in relation to gene regulation, including in bacteria, archaea, mammals and plants. This comparison reveals certain factors as ancestral sculptors of the genome, but also that evolution tolerates considerable variety in genome organization.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1824-1837"},"PeriodicalIF":12.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712799","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":"Structural insights into SV2A and the mechanism of racetam anticonvulsants","authors":"Mazdak M. Bradberry, Edwin R. Chapman","doi":"10.1038/s41594-024-01430-3","DOIUrl":"10.1038/s41594-024-01430-3","url":null,"abstract":"Racetam anticonvulsants, such as levetiracetam, are widely prescribed to treat and prevent seizures. Despite decades of clinical use, their mechanism of action remains unclear. Two studies now reveal the structure of the racetam-binding protein SV2A in complex with anticonvulsant drugs, providing insights into their mechanism of action and the physiology of neurotransmission.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 12","pages":"1818-1820"},"PeriodicalIF":12.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684164","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":"Menopause age and cancer risk is influenced by rare genetic variants","authors":"Michelle Korda","doi":"10.1038/s41594-024-01434-z","DOIUrl":"10.1038/s41594-024-01434-z","url":null,"abstract":"","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"31 11","pages":"1646-1647"},"PeriodicalIF":12.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601002","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}