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Researchers identify new ALS gene and signaling pathways.

CAMBRIDGE, Mass., February 19, 2015 -- Using advanced DNA sequencing methods, scientists and clinicians from Columbia University Medical Center (CUMC), Biogen Idec (BIIB), and HudsonAlpha Institute for Biotechnology have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.

The researchers are using patient-derived, induced pluripotent stem cells (iPS cells) and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates.

The newly associated gene, called TBK1 (TANK-Binding Kinase 1), plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study was published today in the online edition of Science.

ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases.

The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date.

Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases.

"The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn of the ALS Association. "The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today."

The study shows that large-scale genetic studies can not only work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts.

ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which we're only beginning to discover. The more of these mutations that are identified, the better researchers can decipher and influence the pathways that lead to disease.

Searching through the enormous database generated in the ALS study, the researchers found several genes that appear to contribute to ALS, most notably TBK1, which had not been detected in previous, smaller-scale studies.

TBK1 mutations appeared in about one percent of the ALS patients--a large proportion in the context of a complex disease with multiple genetic components, according to Goldstein. The study also found that a gene, called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

The TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS. Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients.

Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor cell survival.



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Title Annotation:Advanced Cell Technology
Publication:Stem Cell Business News
Date:Feb 23, 2015
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