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

Neuron. 2020 Dec 9;108(5):822-842. doi: 10.1016/j.neuron.2020.08.022. Epub 2020 Sep 14.


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.

Keywords: ALS; C9ORF72; FUS; OPTN; SOD1; TARDBP; TBK1; TDP-43; gain of function; loss of function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / therapy*
  • Animals
  • C9orf72 Protein / genetics
  • Forecasting
  • Gain of Function Mutation / genetics*
  • Genetic Therapy / trends*
  • Humans
  • Loss of Function Mutation / genetics*
  • Superoxide Dismutase-1 / genetics


  • C9orf72 Protein
  • C9orf72 protein, human
  • SOD1 protein, human
  • Superoxide Dismutase-1