Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways


IMAGE CAPTION: Dominant not benign variants in TBK1 and OPTN. LoF variants (filled red), non-synonymous variants (filled blue), and splice variants (filled purple) in cases (red lines), controls (blue lines), or cases and controls (dashed lines). (Cirulli & Lasseigne, et al. Science. 2015.)

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.