Second Study Salutes TANK-Binding Kinase 1 as ALS Gene

In February, scientists reported that TANK-binding kinase 1 was a potential amyotrophic lateral sclerosis gene. Now, another research group has arrived at the same conclusion, and even extended the association to frontotemporal dementia. As outlined in the March 24 Nature Neuroscience online, researchers led by senior author Jochen Weishaupt at Ulm University in Germany identified TBK1 mutations in people with familial ALS. Overall, dominant TBK1 mutations made up 4 percent of the familial ALS cases examined. In the study reported last month, TBK1 mutations explained fewer than 2 percent of ALS, though they were mainly sporadic, not inherited, cases (see Feb 2015 news).

TBK1 Domains. Truncations or deletions that eliminate the second of two coiled-coils (ccd 2) seem to cause ALS. [Image courtesy of Frieschmidt et al., Nature Neuroscience.] 

Joint first authors Axel Freischmidt and Wolfgang Ruf at Ulm, Thomas Wieland of Helmholtz Zentrum München in Neuherberg, and Benjamin Richter of Goethe University School of Medicine, Frankfurt, all in Germany, screened the exomes of 252 people with familial ALS, discovering one TBK1 deletion and six nonsense mutations predicted to truncate the protein product. They found another nonsense mutation in one person in a set of 1,010 people with sporadic ALS. Among 4,578 control exomes, they observed one nonsense mutation—in a person who had two relatives with ALS. Eight TBK1 mutations occurred in a further 60,706 exomes from the Exome Aggregation Consortium database, managed by the Broad Institute in Cambridge, Massachusetts. This database includes various exomes from population and disease-specific studies. The authors speculate that those mutation carriers might be from a schizophrenia data set included in that consortium, because ALS and schizophrenia have been linked by a family in which the conditions co-occurred (Gunnarsson et al., 1991).

All told, the researchers—including co-senior authors Tim Strom of Helmholtz Zentrum München and Peter Andersen of Ulm University—identified the eight TBK1 mutations in 13 families (some families shared the same mutation). They examined disease penetrance in seven of those kindreds. Thirty-three carriers were diagnosed with ALS, at an average age of 60 years old. Seven others, aged between 60 and 74, have shown no symptoms. Overall, this suggests a high penetrance, the authors wrote.

Though the majority of affected family members had ALS, half also showed signs of cognitive impairment, some with full-blown frontotemporal dementia. Autopsy brain samples were available from one family member who had died soon after diagnosis. This person had extensive TDP-43 positive inclusions as well as inclusions containing p62, which interacts with TBK1 and is encoded by the ALS gene sequestosome 1.

How might TBK1 mutations cause motor neuron disease? The protein contains a kinase domain, a ubiquitin-like domain, and two coiled-coils (see image above). The authors predicted that the nonsense mutations would result in loss of the protein. Sure enough, when they examined cell lines derived from the patients with the truncations, they observed that TBK1 mRNA and protein were half of the normal levels. TBK1 mutations probably create disease due to haploinsufficiency of the protein, conclude the researchers.

The deletion, which eliminated half of the second coiled-coil, did produce a smaller protein. This allowed Freischmidt and colleagues to investigate which part of TBK1 might be crucial for motor neuron health. The coiled-coil normally interacts with adaptor proteins, including optineurin, which has also been linked to ALS (see May 2010 news). The deletion mutant did not bind optineurin, however, the other domains still seemed to work, because the smaller TBK1 bound and phosphorylated one of its substrates, interferon regulatory factor 1. The authors suspect loss of the second coiled-coil would be sufficient to cause motor neuron disease, though they have not tested that yet in cell or animal models.—Amber Dance

Comments

  1. Freischmidt et al. provide important new data on the role of TBK1 in familial ALS, complementing nicely the recent discovery of TBK1 in a cohort made up largely of patients with sporadic disease.

    The authors show an important link with FTD, which, if confirmed in larger samples, suggests that TBK1 mediates a specific form of ALS. There are also indications in the data that the primary mechanism of pathogenicity is haploinsufficiency, since it appears that many of the mutations are associated with reduced mRNA abundance, presumably due to nonsense mediated decay and reduced protein abundance. This is only the very beginning of our efforts to understand how TBK1 influences risk of disease, and what the precise clinical correlates are, but it is exciting to see new information coming out so soon after its first discovery in ALS.

    View all comments by Richard M. Myers

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References

News Citations

  1. TANK-Binding Kinase 1 Rumbles in as New ALS Gene
  2. Optineurin Mutations Cause ALS, If Not Glaucoma

Paper Citations

  1. Gunnarsson LG, Dahlbom K, Strandman E. Motor neuron disease and dementia reported among 13 members of a single family. Acta Neurol Scand. 1991 Nov;84(5):429-33. PubMed.

External Citations

  1. TANK-binding kinase 1
  2. Exome Aggregation Consortium
  3. sequestosome 1
  4. optineurin

Further Reading

Papers

  1. Wong YC, Holzbaur EL. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4439-48. Epub 2014 Oct 7 PubMed.
  2. Osaka M, Ito D, Yagi T, Nihei Y, Suzuki N. Evidence of a link between ubiquilin 2 and optineurin in amyotrophic lateral sclerosis. Hum Mol Genet. 2015 Mar 15;24(6):1617-29. Epub 2014 Nov 14 PubMed.
  3. Turturro S, Shen X, Shyam R, Yue BY, Ying H. Effects of mutations and deletions in the human optineurin gene. Springerplus. 2014;3:99. Epub 2014 Feb 19 PubMed.
  4. Teyssou E, Takeda T, Lebon V, Boillée S, Doukouré B, Bataillon G, Sazdovitch V, Cazeneuve C, Meininger V, LeGuern E, Salachas F, Seilhean D, Millecamps S. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol. 2013 Apr;125(4):511-22. PubMed.
  5. Gal J, Ström AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW, Zhu H. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem. 2009 Nov;111(4):1062-73. PubMed.

Primary Papers

  1. Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, Marroquin N, Nordin F, Hübers A, Weydt P, Pinto S, Press R, Millecamps S, Molko N, Bernard E, Desnuelle C, Soriani MH, Dorst J, Graf E, Nordström U, Feiler MS, Putz S, Boeckers TM, Meyer T, Winkler AS, Winkelman J, de Carvalho M, Thal DR, Otto M, Brännström T, Volk AE, Kursula P, Danzer KM, Lichtner P, Dikic I, Meitinger T, Ludolph AC, Strom TM, Andersen PM, Weishaupt JH. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. 2015 May;18(5):631-6. Epub 2015 Mar 24 PubMed.

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