{"title":"抗Legumain/天冬氨酰内肽酶的tau纤维折叠可产生皮质基底变性特异性C端tau片段。","authors":"Daisuke Taniguchi, Shotaro Shimonaka, Ahmed Imtiaz, Montasir Elahi, Taku Hatano, Yuzuru Imai, Nobutaka Hattori","doi":"10.1016/j.nbd.2024.106686","DOIUrl":null,"url":null,"abstract":"<p><p>Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils. Tau fibrils from patients with CBD were amplified in non-astrocytic cultured cells, which maintained CBD-specific biochemical properties. We found that the lysosomal protease Legumain (LGMN) was involved in the generation of CBD-specific 37-40-kDa CTFs. While LGMN cleaved tau fibrils at Asn167 and Asn368 in the brain tissues of patients with Alzheimer's disease and PSP, tau fibrils from patients with CBD were predominantly resistant to cleavage at Asn368 by LGMN, resulting in the generation of CBD-specific CTFs. LGMN preference in tau fibrils was lost upon unraveling the tau fibril fold, suggesting that the CBD-specific tau fibril fold contributes to CBD-specific CTF production. From these findings, we found a way to differentiate astrocytic plaque from tufted astrocyte using the anti-Asn368 LGMN cleavage site-specific antibody. Inoculation of tau fibrils amplified in non-astrocytic cells into the mouse brain reproduced LGMN-resistant tau fibrils and recapitulated anti-Asn368-negative astrocytic plaques, which are characteristic of CBD pathology. This study supports the existence of disease-specific tau fibrils and contribute to further understanding of the tauopathy diagnosis. Our tau propagation mouse model using cellular tau seeds may contribute to uncovering disease mechanisms and screening for potential therapeutic compounds.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Legumain/asparaginyl endopeptidase-resistant tau fibril fold produces corticobasal degeneration-specific C-terminal tau fragment.\",\"authors\":\"Daisuke Taniguchi, Shotaro Shimonaka, Ahmed Imtiaz, Montasir Elahi, Taku Hatano, Yuzuru Imai, Nobutaka Hattori\",\"doi\":\"10.1016/j.nbd.2024.106686\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils. Tau fibrils from patients with CBD were amplified in non-astrocytic cultured cells, which maintained CBD-specific biochemical properties. We found that the lysosomal protease Legumain (LGMN) was involved in the generation of CBD-specific 37-40-kDa CTFs. While LGMN cleaved tau fibrils at Asn167 and Asn368 in the brain tissues of patients with Alzheimer's disease and PSP, tau fibrils from patients with CBD were predominantly resistant to cleavage at Asn368 by LGMN, resulting in the generation of CBD-specific CTFs. LGMN preference in tau fibrils was lost upon unraveling the tau fibril fold, suggesting that the CBD-specific tau fibril fold contributes to CBD-specific CTF production. From these findings, we found a way to differentiate astrocytic plaque from tufted astrocyte using the anti-Asn368 LGMN cleavage site-specific antibody. Inoculation of tau fibrils amplified in non-astrocytic cells into the mouse brain reproduced LGMN-resistant tau fibrils and recapitulated anti-Asn368-negative astrocytic plaques, which are characteristic of CBD pathology. This study supports the existence of disease-specific tau fibrils and contribute to further understanding of the tauopathy diagnosis. Our tau propagation mouse model using cellular tau seeds may contribute to uncovering disease mechanisms and screening for potential therapeutic compounds.</p>\",\"PeriodicalId\":19097,\"journal\":{\"name\":\"Neurobiology of Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2024-09-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurobiology of Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.nbd.2024.106686\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.nbd.2024.106686","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
皮质基底层变性(CBD)与进行性核上性麻痹(PSP)一样,是一种主要的四重复tau病。虽然去污剂不溶性的37-40-kDa羧基末端tau片段(CTFs)是CBD病理学的标志,但其形成过程尚不清楚。本研究利用CBD型纤维与阿尔茨海默病/PSP型纤维不同的生化特性,监测了CBD型纤维的形成过程,CBD病理特征之一是星形胶质斑块。来自 CBD 患者的 Tau 纤维在非星形细胞培养细胞中得到扩增,并保持了 CBD 特有的生化特性。我们发现溶酶体蛋白酶Legumain(LGMN)参与了CBD特异性37-40-kDa CTFs的生成。在阿尔茨海默氏症和帕金森氏症患者的脑组织中,LGMN能在Asn167和Asn368处裂解tau纤维,而CBD患者的tau纤维则主要对LGMN在Asn368处的裂解具有抵抗力,从而产生了CBD特异性CTFs。在解开tau纤维折叠后,LGMN对tau纤维的偏好就消失了,这表明CBD特异性tau纤维折叠有助于CBD特异性CTF的产生。根据这些发现,我们找到了一种利用抗Asn368 LGMN裂解位点特异性抗体区分星形胶质细胞斑块和丛星形胶质细胞的方法。将在非星形胶质细胞中扩增的 tau 纤维接种到小鼠大脑中,可再现抗 LGMN 的 tau 纤维,并再现抗Asn368 阴性的星形胶质细胞斑块,这是 CBD 病理学的特征。这项研究证实了疾病特异性tau纤维的存在,有助于进一步了解tau病的诊断。我们利用细胞tau种子建立的tau传播小鼠模型可能有助于揭示疾病机制和筛选潜在的治疗化合物。
Legumain/asparaginyl endopeptidase-resistant tau fibril fold produces corticobasal degeneration-specific C-terminal tau fragment.
Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils. Tau fibrils from patients with CBD were amplified in non-astrocytic cultured cells, which maintained CBD-specific biochemical properties. We found that the lysosomal protease Legumain (LGMN) was involved in the generation of CBD-specific 37-40-kDa CTFs. While LGMN cleaved tau fibrils at Asn167 and Asn368 in the brain tissues of patients with Alzheimer's disease and PSP, tau fibrils from patients with CBD were predominantly resistant to cleavage at Asn368 by LGMN, resulting in the generation of CBD-specific CTFs. LGMN preference in tau fibrils was lost upon unraveling the tau fibril fold, suggesting that the CBD-specific tau fibril fold contributes to CBD-specific CTF production. From these findings, we found a way to differentiate astrocytic plaque from tufted astrocyte using the anti-Asn368 LGMN cleavage site-specific antibody. Inoculation of tau fibrils amplified in non-astrocytic cells into the mouse brain reproduced LGMN-resistant tau fibrils and recapitulated anti-Asn368-negative astrocytic plaques, which are characteristic of CBD pathology. This study supports the existence of disease-specific tau fibrils and contribute to further understanding of the tauopathy diagnosis. Our tau propagation mouse model using cellular tau seeds may contribute to uncovering disease mechanisms and screening for potential therapeutic compounds.
期刊介绍:
Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.