Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains
Mingee Chung, Kathleen Carter, Austin M. Veire, Eric B. Dammer, Jianjun Chang, Duc M. Duong, Nisha Raj, Gary J. Bassell, Jonathan D. Glass, Tania F. Gendron, Peter T. Nelson, Allan I. Levey, Nicholas T. Seyfried, Zachary T. McEachin
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.