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

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.

HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases

“…Loss of TDP-43 from the nucleus impairs its ability to repress cryptic exon (CE) inclusion during RNA splicing [ 1 ]. Consequently, CEs are anomalously included in critical transcripts such as STMN2 and UNC13A [ 2 – 9 ], which can produce truncated or destabilized RNAs and lead to a loss of their function. Recently, we and others demonstrated that some transcripts with in-frame CEs produce stable CE-containing novel proteins detectable in cerebrospinal fluid (CSF) from patients with FTLD-TDP or ALS [ 10 , 11 ].…”

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominance and reveals potential modulating targets

“…TDP-43 is a major mRNA splicing regulator, and changes in splicing are found in TDP-43 proteinopathies including ALS, FTLD-TDP, and LATE ( Chang et al, 2023 ; Chung et al, 2024 ; Mehta et al, 2023 ). We evaluated transcriptomic data from tau Tg, TDP-43 Tg, and tau-TDP-43 Tg animals for alternative splicing using established analysis methods (DEXSeq and SpliceWiz) ( Anders et al, 2012 ; Wong et al, 2024 ).…”

Elevated nuclear TDP-43 induces constitutive exon skipping

“…3 B). AD cases without TDP-43 inclusions may still exhibit cryptic exons ( STMN2 ) due to the observation of TDP-43 nuclear clearance without cytoplasmic aggregation [ 24 , 67 , 68 ]. However, skipping events in at least three genes ( HYOU1 , NUP93 , and XPNPEP1 ) could be detected in both disease cases and controls.…”