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CRYPTIC SPLICING OF STATHMIN-2 AND UNC13A MRNAS IS A PATHOLOGICAL HALLMARK OF TDP-43-ASSOCIATED ALZHEIMER’S DISEASE
Abstract
Aims
Overwhelming evidence supports that Alzheimer’s disease (AD) has a heterogeneous etiology, underscoring the need to stratify AD patients into subgroups according to their pathological status. Cytoplasmic inclusions of phosphorylated TDP-43 are a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Notably, TDP-43 proteinopathy is also present in approximately half of AD cases. In AD, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. We aim to explore the impact of TDP-43 pathology and its associated loss of function in AD.
Methods
Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts, including Stathmin-2 (STMN2) and UNC13A. Here, we achieved different levels of TDP-43 suppression to dissect the sensitivity of UNC13A and STMN2 cryptic exons to TDP-43 loss-of-function. We then determined the presence of STMN2 and UNC13A aberrant transcripts in AD by performing qRT-PCR in post-mortem brain tissue (38 AD patients and 14 controls), and by mining RNA seq datasets (more than 500 AD patients).
Results
Processing of the STMN2 pre-mRNA was shown to be more sensitive to TDP-43 loss of function than UNC13A. We also demonstrated that both STMN2 and UNC13A cryptic exons accumulate in tissues from AD patients. Misprocessing of STMN2 and UNC13A correlates with TDP-43 pathology burden, but not with amyloid-β or tau deposits. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from AD post-mortem brain tissue.
Conclusions
These results open exciting avenues to use STMN2 and UNC13A as potential therapeutic targets in AD and highlight the potential of TDP-43-dependent splicing alterations as molecular markers to subgroup AD patients.