Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains

• Type of Material: Article
• Authors: Mingee Chung, Emory University; E. Kathleen Carter, Emory University; Austin M. Veire, Mayo Clinic, Jacksonville; Eric B Dammer, Emory University; Jianjun Chang, Emory University; Duc Duong, Emory University; Nisha Raj, Emory University; Gary Bassell, Emory University; Jonathan D Glass, Emory University; Tania F. Gendron, Mayo Clinic, Jacksonville; Peter T. Nelson, University of Kentucky; Allan I Levey, Emory University; Nicholas Seyfried, Emory University; Zachary Mceachin, Emory University
• Language: English
• Date: 2024-02-03
• Publisher: Springer Nature Link
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2024
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1007/s00401-023-02671-0
• Title of Journal or Parent Work: Acta Neuropathologica
• Volume: 147
• Start Page: 29
• Grant/Funding Information: JDG was supported by the National Institute of Neurological Disorders and Stroke, 5P01NS084974-07. NTS was supported by 5P01NS084974-07, National Institute of Aging, P30AG066511-04 and U01AG061357. AIL was supported by National Institute of Aging, U01AG061357. MC, NR, GJB, ZTM were supported by the Emory University School of Medicine Laboratory for Translational Cell Biology.; This work was supported by National Institute for Neurological Disorders and Stroke 5P01NS084974-07 (N.T.S., J.D.G), the National Institute of Aging P30AG066511-04 (A.I.L.); U01AG061357 (A.I.L., N.T.S.), and the Emory University School of Medicine Laboratory for Translational Cell Biology (M.C., N.R., G.J.B., Z.T.M.)
• Keywords: TDP-43; Alzheimer’s disease; LATE-NC; Cryptic exons
• Research Categories: Psychology, Cognitive; Biology, Neuroscience; Health Sciences, Pathology

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.