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

Garam Kim 1, Olivia Gautier 1, Eduardo Tassoni-Tsuchida 2, X Rosa Ma 3, Aaron D Gitler 4

Affiliations

PMID: 32931756
DOI: 10.1016/j.neuron.2020.08.022

Abstract

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.

Conflict of interest statement

Declaration of Interests A.D.G. has served as a consultant for Aquinnah Pharmaceuticals, Prevail Therapeutics, and Third Rock Ventures and is a scientific founder of Maze Therapeutics.

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