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

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• TDP-43 proteinopathies, including Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), are characterized by TDP-43 aggregation and mislocalization.
• LATE neuropathologic changes (LATE-NC) frequently co-occur with other neurodegenerative conditions like Alzheimer's disease neuropathologic changes (ADNC).

Purpose of the Study:

• To investigate the accumulation of TDP-43 regulated cryptic exons in the hippocampus of LATE-NC cases.
• To determine if cryptic RNAs can serve as biomarkers for LATE, particularly in cases with comorbid ADNC.

Main Methods:

• Analysis of neuropathologically confirmed LATE-NC cases, including those with and without ADNC, and comparison with healthy controls and AD cases.
• Quantification and correlation of cryptic RNA expression with phosphorylated TDP-43 (pTDP-43) abundance.

Main Results:

• Several cryptic RNAs were robustly expressed in LATE-NC cases, correlating with pTDP-43 levels.
• Cryptic RNA accumulation was more pronounced in LATE-NC cases with comorbid ADNC.
• Cryptic RNAs effectively distinguished LATE-NC from healthy controls and AD cases.

Conclusions:

• TDP-43 regulated cryptic RNAs are significantly expressed in LATE.
• These cryptic RNAs show potential as novel biomarkers for diagnosing LATE and understanding its pathogenesis, especially in comorbid conditions.