ALS Genetics: Gains, Losses, and Implications for Future Therapies.

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. In this review, Kim et al. discuss evidence for loss-of-function mutations and mechanisms in amyotrophic lateral sclerosis (ALS) and propose the need to consider both gain and loss of function for designing effective and safe therapeutic strategies. [ABSTRACT FROM AUTHOR]