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

Author:

Ma X. RosaORCID,Prudencio MercedesORCID,Koike YukaORCID,Vatsavayai Sarat C.,Kim GaramORCID,Harbinski Fred,Briner AdamORCID,Rodriguez Caitlin M.,Guo Caiwei,Akiyama TetsuyaORCID,Schmidt H. Broder,Cummings Beryl B.,Wyatt David W.,Kurylo Katherine,Miller Georgiana,Mekhoubad Shila,Sallee Nathan,Mekonnen Gemechu,Ganser Laura,Rubien Jack D.ORCID,Jansen-West Karen,Cook Casey N.,Pickles Sarah,Oskarsson BjörnORCID,Graff-Radford Neill R.,Boeve Bradley F.ORCID,Knopman David S.ORCID,Petersen Ronald C.,Dickson Dennis W.ORCID,Shorter James,Myong Sua,Green Eric M.ORCID,Seeley William W.,Petrucelli Leonard,Gitler Aaron D.ORCID

Abstract

AbstractA 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 splicing2–4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, 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 inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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