The ALS Association

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Carrie Munk
The ALS Association
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ALS Research Highlights from the Society for Neuroscience

Washington, D.C. (November 4, 2015) — The 2015 Annual Meeting of the Society for Neuroscience (SFN), held in October in Chicago, provided ALS researchers an opportunity to present new science, exchange ideas, and forge new collaborations in the effort to develop new therapies for ALS. The meeting focuses on basic neuroscience, the source for major new theories of disease and new understanding of cell processes that can lead to new treatments.

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

The 10th Brain Research Conference entitled “RNA Metabolism in Neurological Disease,” organized by Dr’s Paul Taylor and Fen-Biao Gao, was held as a two day satellite meeting to the SFN. The meeting was heavily focused on ALS. RNA, a key molecule in many cell processes, is believed to play an important role in ALS. The C9orf72 gene mutation creates excess RNA that may contribute to disease pathogenesis, and ALS results from mutations in two RNA-processing proteins, TDP-43 and FUS. C9orf72 mouse models were presented by numerous laboratories. These models share some similarities but also significant differences. Understanding why these models differ and how they can be used to better understand disease mechanism associated with the repeat expansion will be extremely valuable for the field. In addition, data generated from a variety of labs highlights the abnormalities in nuclear transport in model systems and in motor neurons derived from induced pluripotent stem cells from ALS patients. These themes were reiterated as discussed below at the main SFN meeting.

Among the research highlights presented at the satellite meeting and the SFN meeting were [including links to the presentation abstract]:

Growing Excitement about Nuclear Transport as a Key Deficit in C9orf72 ALS
Recent work from multiple laboratories has revealed that the C9orf72 mutation, the most common genetic cause of ALS, interferes with trafficking of materials in and out of the cell nucleus. This interference may have profound effects on the function of cells, including motor neurons, and may point to a major pathway for disease.

New research presented at the meeting added some details to this picture, with researchers showing specific effects on nuclear transport molecules due to the mutation. Mitigating these effects may be therapeutic, and looking more deeply at the cascade of problems caused by these effects may reveal new targets for therapy.

One likely consequence of these transport defects is to strand a protein called TDP-43 outside of the nucleus, where it aggregates and becomes nonfunctional. One role for TDP-43 in the nucleus is to suppress the use of gene segments that are not meant to be “read” when making instructions for proteins. Use of these segments, called “cryptic exons,” leads to degradation of the protein instructions, likely causing multiple problems. For more detail please view our recent webinar featuring Dr. Phillip Wong’s research.

Other toxic effects of the mutation were also explored, including the tendency of the mutation to interfere with proper formation of a receptor for glutamate. Glutamate is a neurotransmitter, important for communication between neurons. Interference with receptor synthesis may lead neurons to become improperly regulated by other neurons, increasing the likelihood of their death.

The C9orf72 mutation also causes production of unusual proteins called “dipeptide repeat proteins” (DRPs). Researchers presented new data showing that DRPs may be toxic to neurons, possibly by interfering with a critical cell structure called the nucleolus.

Elsewhere, researchers explored the normal function of the C9orf72 protein, suggesting it may interact with nuclear import proteins.

Other Highlights of New Research

  • A new model of SOD1-related ALS indicates that mutant protein can be transferred from neuron to neuron in mice, which may contribute to the spread of the disease.
  • The TDP-43 protein can also be transferred between neurons, and may promote its aggregation. Aggregation of TDP-43 is a common feature in many forms of ALS.
  • Levels of a protein called chitotriosidase in the cerebrospinal fluid may be a valuable biomarker for ALS. Researchers showed it was strongly elevated in people with ALS compared to controls following diagnosis. Ongoing studies will determine whether its levels change with disease progression, which would make it a valuable way to track disease and response to treatment.
  • The experimental chemotherapeutic masitinib slows decline in a rat model of ALS when delivered after onset of symptoms, probably through inhibition of neuroinflammation. The drug is in a trial in Europe and South America.
  • A new mouse model of ALS includes mutation in an important cell transport protein called tau. The form of tau used in the mice is the same as that found in people with ALS who develop cognitive impairment. This should make the model useful for studying the development of cognitive effects of ALS.
  • Researchers have developed a gene therapy vehicle called AAV2, which can selectively target motor neurons in the brain. This will be valuable in the study of upper motor neurons, which are increasingly seen as an important subset of affected neurons in ALS. The AAV2 vehicle will allow researchers to deliver various genes to the motor neurons to study their effects on these cells in the disease. It also may provide a platform for delivery of treatments, after further development.
  • A new mouse model of ALS due to profilin mutation indicates the disease can develop when a cell transport protein called actin cannot form long chains. The model should be useful for understanding the consequences of transport defects in ALS, which are thought to contribute to some forms of the disease.

About The ALS Association
The ALS Association is the only national non-profit organization fighting Lou Gehrig’s Disease on every front. By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, The Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure. For more information about The ALS Association, visit our website at

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