New ALS gene, signaling pathways identified

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There’s good news on ALS and this time it’s far more happening than the Ice Bucket Challenge! We say this not just about the research but also the way in which it was carried out. Here’s a research model where the industry experts and the academia i.e. the clinicians and scientists came together in a collaborative effort to find a breakthrough in the workings of ALS.

Amyotrophic lateral sclerosis or ALS is a genetic neurodegenerative disorder that affects the voluntary movements of an individual and is fatal in almost all cases. For this study, genetic sequencing of the protein-coding portions (exomes) of 2,874 ALS patients and 6,405 controls was carried out- the largest number of ALS patients to have been sequenced in a single study till date.

While screening the enormous database generated from this study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. More importantly, this gene accounts for 1% of ALS which is a large proportion in a complex multiple genetic disorder. TBK1 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).

Induced pluripotent stem cell-derived motor neurons from an ALS patient (left) compared with normal cells (right). The cells are being used to study the role of the genes TBK1 and OPTN in ALS. (Credit: Laboratory of Tom Maniatis/Columbia University Medical Center)
Induced pluripotent stem cell-derived motor neurons from an ALS patient (left) compared with normal cells (right). The cells are being used to study the role of the genes TBK1 and OPTN in ALS. (Credit: Laboratory of Tom Maniatis/Columbia University Medical Center)

“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, PhD, Chief Scientist for the ALS Association. Also, the gene OPTN which was previously considered to play a minor role is now suspected to play a major role in this disease.

“This study shows us that large-scale genetic studies not only can 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,” said study co-leader David B. Goldstein, PhD, professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC. “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 we identify, the better we can decipher—and influence—the pathways that lead to disease.” The other co-leaders of the study are Richard M. Myers, PhD, president and scientific director of HudsonAlpha, and Tim Harris, PhD, DSc, Senior Vice President, Technology and Translational Sciences, Biogen Idec.

“I love this research model because it doesn’t happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind. The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done”, said Dr. Myers.

It’s clear that a common ALS treatment may not work on all patients for such a diverse genetic disorder. Hence, targeted treatment i.e customized treatment for each ALS patient on the basis of the specific underlying cause may be the only way forward. As David Goldstein rightly points out this is just the tip of the iceberg. A long way to go before we succeed in realizing the real purpose behind the Ice Bucket Challenge!

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The original publication can be accessed here.

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