CRYPTIC EXONS AS MARKERS FOR TDP-43 PROTEINOPATHY

The discovery of aberrant inclusions of TDP-43 in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), significantly changed the field of neurodegeneration. Notably, TDP-43 proteinopathy is also present in approximately half of alzheimer’s disease (AD) cases. In AD, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Even though TDP-43 is recognized as an important pathological hallmark of disease, how TDP-43 leads to neuronal dysfunction in AD remains largely unknown.
Predominantly nuclear, TDP-43 is an RNA binding protein, and loss of nuclear TDP-43 has been consistently shown to affect the cell transcriptome. Loss of TDP-43 function causes misprocessing of multiple pre-mRNAs, including Stathmin-2 (STMN2) and UNC13A, leading to cryptic exon inclusion in post-mortem ALS and FTD tissue and directly linking TDP-43 dysfunction to disease-relevant molecular defects.
We aimed to explore the impact of TDP-43 pathology and its associated loss of function in AD. Our results show that STMN2 pre-mRNA processing is more sensitive to TDP-43 loss than UNC13A. We also detected accumulation of cryptic exons in both STMN2 and UNC13A transcripts in AD patients, which correlates with TDP-43 pathology but not with amyloid-β or tau deposits. In addition, full-length STMN2 and UNC13A RNAs are reduced in large RNA-seq datasets from AD post-mortem brains. Finally, we are investigating how TDP-43 pathology interacts with other AD-related pathologies to drive network dysfunction, positioning TDP-43–dependent RNA misprocessing as a central determinant of neuronal vulnerability in Alzheimer’s disease.