Elizabeth T. Cirulli, Brittany N. Lasseigne, Slavé Petrovski, Peter C. Sapp, Patrick A. Dion, Claire S. Leblond, Julien Couthouis, Yi-Fan Lu, Quanli Wang, Brian J. Krueger, Zhong Ren, Jonathan Keebler, Yujun Han, Shawn E. Levy, Braden E. Boone, Jack R. Wimbish, Lindsay L. Waite, Angela L. Jones, John P. Carulli, Aaron G. Day-Williams, John F. Staropoli, Winnie W. Xin, Alessandra Chesi, Alya R. Raphael, Diane McKenna-Yasek, Janet Cady, J. M. B. Vianney de Jong, Kevin P. Kenna, Bradley N. Smith, Simon Topp, Jack Miller, Athina Gkazi, FALS Sequencing Consortium, Ammar Al-Chalabi, Leonard H. van den Berg, Jan Veldink, Vincenzo Silani, Nicola Ticozzi, Christopher E. Shaw, Robert H. Baloh, Stanley Appel, Ericka Simpson, Clotilde Lagier-Tourenne, Stefan M. Pulst, Summer Gibson, John Q. Trojanowski, Lauren Elman, Leo McCluskey, Murray Grossman, Neil A. Shneider, Wendy K. Chung, John M. Ravits, Jonathan D. Glass, Katherine B. Sims, Vivianna M. Van Deerlin, Tom Maniatis, Sebastian D. Hayes, Alban Ordureau, Sharan Swarup, John Landers, Frank Baas, Andrew S. Allen, Richard S. Bedlack, J. Wade Harper, Aaron D. Gitler, Guy A. Rouleau, Robert Brown, Matthew B. Harms, Gregory M. Cooper, Tim Harris, Richard M. Myers, David B. Goldstein
Science 347: 1436-1441, 2015. PMCID: PMC4437632
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.