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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by the loss of motor neurons from the brain and spinal cord. The ALS community has made remarkable strides over three decades by identifying novel familial mutations, generating animal models, elucidating molecular mechanisms, and ultimately developing promising new therapeutic approaches. Some of these approaches reduce the expression of mutant genes and are in human clinical trials, highlighting the need to carefully consider the normal functions of these genes and potential contribution of gene loss-of-function to ALS. Here, we highlight known loss-of-function mechanisms underlying ALS, potential consequences of lowering levels of gene products, and the need to consider both gain and loss of function to develop safe and effective therapeutic strategies.

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 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.