Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Institute On Aging, Perelman School of Medicine, University of Pennsylvania, 613A Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA, 19104, USA.
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Acta Neuropathol. 2024 Jun 19;147(1):104. doi: 10.1007/s00401-024-02753-7.
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.
TAR DNA 结合蛋白 43（TDP-43）是一种 RNA 结合蛋白，存在于与衔接蛋白 A11 相连的核仁蛋白颗粒中。TDP-43 蛋白在许多神经退行性疾病中形成包含物，包括肌萎缩侧索硬化症（ALS）、伴有 TDP-43 包含物的额颞叶变性（FTLD-TDP）和边缘为主的与年龄相关的 TDP-43 脑病神经病理改变（LATE-NC）。衔接蛋白 A11 也已知在 ALS 病例中形成聚集体，这些病例中存在 ANXA11 的致病性变异。在散发性 ALS、FTLD-TDP 或 LATE-NC 病例中尚未描述衔接蛋白 A11 聚集。为了探讨 TDP-43 与衔接蛋白 A11 之间的关系，对 822 例尸检病例进行了基因分析，以鉴定罕见的 ANXA11 变体。此外，对 368 例尸检病例进行了免疫组织化学研究，以鉴定衔接蛋白 A11 聚集体。在所有 FTLD-TDP 型 C 病例中，均存在与 TDP-43 包含物共定位的不溶性衔接蛋白 A11 聚集体。在散发性和遗传性 FTLD-TDP 型 A 和 B、ALS 和 LATE-NC 的一小部分（3-6%）病例中也观察到衔接蛋白 A11 包含物。此外，我们在患有致病性 ANXA11 p.G38R 变异的 ALS 病例中证实了衔接蛋白 A11 和 TDP-43 聚集体的混合。最后，我们在一例由于新型变异 ANXA11 p.P75S 导致的以突出纹状体空泡化为特征的进行性核上性麻痹样额颞叶痴呆病例中发现了大量的衔接蛋白 A11 包含物，这是主要的病理发现。通过免疫印迹，伴有衔接蛋白病和 ANXA11 变异的 FTLD-TDP 病例显示不溶性衔接蛋白 A11 的积累，包括截断片段。这些结果表明，衔接蛋白 A11 在散发性和遗传性 TDP-43 蛋白病中形成了多种多样的聚集体。此外，由于 ANXA11 p.P75S 导致的原发性空泡性衔接蛋白病的发现表明，衔接蛋白 A11 聚集足以引起神经退行性变。
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