Abstract

The aggregation, mislocalization, and phosphorylation of TDP-43 are pathologic hallmarks of several neurodegenerative diseases and provide a defining criterion for the neuropathologic diagnosis of Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). LATE neuropathologic changes (LATE-NC) are often comorbid with other neurodegenerative pathologies including Alzheimer’s disease neuropathologic changes (ADNC). We examined whether TDP-43 regulated cryptic exons accumulate in the hippocampus of neuropathologically confirmed LATE-NC cases. We found that several cryptic RNAs are robustly expressed in LATE-NC cases with or without comorbid ADNC and correlate with pTDP-43 abundance; however, the accumulation of cryptic RNAs is more robust in LATE-NC with comorbid ADNC. Additionally, cryptic RNAs can robustly distinguish LATE-NC from healthy controls and AD cases. These findings expand our current understanding and provide novel potential biomarkers for LATE pathogenesis.

中文翻译：

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隐秘外显子包含是衰老大脑中 LATE-NC 的分子特征

摘要

TDP-43 的聚集、错误定位和磷酸化是多种神经退行性疾病的病理标志，并为边缘系统主导的年龄相关性 TDP-43 脑病 (LATE) 的神经病理学诊断提供了定义标准。晚期神经病理改变（LATE-NC）通常与其他神经退行性病变共存，包括阿尔茨海默氏病神经病理改变（ADNC）。我们检查了 TDP-43 调节的隐性外显子是否在神经病理学确诊的 LATE-NC 病例的海马中积累。我们发现一些隐性 RNA 在伴有或不伴有 ADNC 共病的 LATE-NC 病例中强烈表达，并且与 pTDP-43 丰度相关；然而，在患有 ADNC 的 LATE-NC 中，隐性 RNA 的积累更为强劲。此外，隐性 RNA 可以强有力地将 LATE-NC 与健康对照和 AD 病例区分开来。这些发现扩展了我们目前的理解，并为晚期发病机制提供了新的潜在生物标志物。