TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.

ABSTRACT: A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord¹. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing^2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies^5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inc

SUBMITTER: Ma XR 

PROVIDER: S-EPMC8891019 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature