Advances in ALS and FTD Genetics Workshop: Report from the Society for Neuroscience Meeting

November 24, 2014

Data, and lots of it, is increasingly seen as critical to finding new treatments for ALS. Data from genes, from tissue samples, and from clinic visits—all of it may hold important clues to what causes amyotrophic lateral sclerosis (ALS), how it progresses, and what determines the onset and development of the disease.

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The ALS Association booth at this year’s Society for Neuroscience conference in Washington, D.C.

Understanding how best to use and share the emerging mountain of ALS data was the theme of The ALS Association-sponsored Advances in ALS and FTD (frontotemporal dementia) Genetics Workshop, held recently in Washington, DC, in conjunction with the annual meeting of the Society for Neuroscience, the largest gathering of neuroscientists in the world. The meeting was co-sponsored by the National Institute of Neurological Disorders and Stroke, and the Association for Frontotemporal Degeneration.

A key goal of the meeting was to develop partnerships and collaborations to increase data sharing. Data sharing has become even more important with the discovery of the C9orf72 gene, which can cause both ALS and FTD. Researchers who specialize in ALS have a lot to learn from those who specialize in FTD and vice versa.

Data sharing is especially important in the hunt for new genes that cause ALS. Combing the genome for genes that contribute to ALS risk depends on having thousands of samples, so that a weak but important genetic “signal” can rise above the background “noise.” Much of the day’s discussion was devoted to discussing how groups currently seeking new ALS genes can work together, and how clinicians can speed their efforts, through careful documentation at each clinic visit of important patient variables such as strength and respiratory function. When such data from hundreds or thousands of people with ALS is combined, it can help researchers better understand how specific genes contribute to disease progression or protection.

The ALS Association is supporting multiple gene discovery networks and encouraging the sharing of data among them, efforts that have begun to bear fruit in the discovery of new ALS risk genes. Further work will be needed to make even bigger strides in understanding ALS. That work is being carried out by national and international consortia, including Project MinE, the 1,000 Exomes Project, the Biogen Idec Genetics Consortium, the European Early-Onset Dementia Consortium, the NIA-European Collaboration, the Genetic FTD Initiative, and the Mayo Clinic.

“Our goal from this workshop was to maximize data sharing and collaboration,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D., M.B.A. “It was especially important to hear from the scientists on what they need most to make those collaborations productive. We did that and will now continue to accelerate this effort both through our funding and our ability to bring different groups together.”

ALS was also a key topic elsewhere at the Society for Neuroscience meeting, with dozens of new research findings presented over five days. Among the highlights was a presentation by ALS Association-supported Safenowitz Fellow Ke Zhang, Ph.D., of Johns Hopkins University, who showed that the C9orf72 gene mutation causes a mislocalization of a key protein called RanGAP, which is critical for transport of many different proteins in and out of the cell nucleus. Efforts to restore RanGAP to its proper place in the cell may be therapeutically valuable.

The full spectrum of C9orf72 research was explored elsewhere in a session describing the latest advances in genetics, pathogenesis, and biomarkers stemming from the discovery of the gene. Among the advances discussed was the potential of the so-called RAN proteins to serve as biomarkers of disease progression. These unusual proteins are made from the mutant gene and can be detected in the cerebrospinal fluid. Leonard Petrucelli, Ph.D., of Mayo Clinic Jacksonville, reported that the levels of a particular RAN protein rose over time in the six people with ALS for whom multiple measurements were available. If this finding is confirmed in larger groups of people, it may be a useful correlate of disease progression and potentially a marker for anti-C9 therapies.

Also of great interest was work presented by Yvette Wong, Ph.D., of the University of Pennsylvania, who showed that the optineurin protein, mutations in which cause ALS, interacts with the parkin protein, mutations in which cause Parkinson’s disease. Both proteins are involved in recycling damaged cell components. The fact that these two proteins work together, and that each causes a neurodegenerative disease when mutated, suggests this pathway may be a critical one for preventing loss of neurons.

Elsewhere, Mahmoud Kiaei, Ph.D., of the University of Arkansas, described a new mouse model of ALS based on the mutant profilin gene, a recently discovered cause of familial ALS. Profilin is a protein that helps build the “cytoskeleton,” the internal protein structure of the cells that gives it shape, allows it to move and transports materials within it. Cytoskeletal defects have been previously implicated in ALS, strengthening the interest in the newly discovered gene. Dr. Kiaei is currently further characterizing the mouse model, in order to learn more about how the mutation leads to disease.

Indeed, a major theme of much of the new science presented was the development and investigation of new models, each of which offers something unique in understanding some aspect of the ALS disease process. New work was brought forth on induced pluripotent stem cell (iPS cell) models of ALS, along with new genes in worms and new studies of mouse models.

“Different models are critically important in understanding different aspects of ALS, and we benefit from each of the new models that our researchers develop. Putting together insights from the various models allows us to understand the contribution of different processes to the overall disease process,” Dr. Bruijn said.

Other ALS-related studies presented examined the role of ALS genes in DNA repair, the contributions of the immune system to disease progression, the mechanism of potentially protective genes in ALS, and a search for other clinical and cellular clues to predicting disease progression.

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