PDF(Pubmed)
Abstract：
TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.
摘要：
TARDNA结合蛋白43（TDP-43）是一种RNA结合蛋白，存在于核糖核蛋白颗粒中，通过膜联蛋白A11与溶酶体相连。TDP-43蛋白在许多神经退行性疾病中形成内含物，包括肌萎缩侧索硬化症（ALS），额颞叶变性伴TDP-43包涵体（FTLD-TDP）和边缘占优势的年龄相关性TDP-43脑病神经病理变化（LATE-NC）。还已知膜联蛋白A11在ALS病例中与ANXA11中的致病变体形成聚集体。膜联蛋白A11聚集在零星的ALS中未被描述，FTLD-TDP或LATE-NC病例。为了探索TDP-43与膜联蛋白A11之间的关系，对822例尸检病例进行了遗传分析，以鉴定罕见的ANXA11变异。此外,我们对368例尸检病例进行了免疫组织化学研究,以鉴定膜联蛋白A11聚集体.在所有FTLD-TDPC型病例中都存在与TDP-43包裹体共同定位的不溶性膜联蛋白A11聚集体。膜联蛋白A11包涵体也在FTLD-TDP类型A和B的零星和遗传形式的一小部分（3-6％）中发现，ALS,Late-NC此外,我们证实了在ALS病例中膜联蛋白A11和TDP-43聚集体与致病性ANXA11p.G38R变体的混合。最后,我们发现大量的膜联蛋白A11内含物作为进行性核上性麻痹样额颞叶痴呆的主要病理发现，由于一种新的变体而出现明显的纹状体空泡化，ANXA11p.P75S.通过免疫印迹,具有膜联蛋白病和ANXA11变体病例的FTLD-TDP显示不溶性ANXA11的积累，包括截短的片段。这些结果表明，膜联蛋白A11在TDP-43蛋白质病的散发性和遗传形式中都形成了多样化和异质范围的聚集体。此外,由ANXA11p.P75S引起的原发性空泡膜联蛋白病的发现表明膜联蛋白A11聚集足以引起神经变性。
