The ALS Association

ALS Ice Bucket Challenge Progress

ALS Research is Featured at World’s Largest Scientific Meeting, Society for Neuroscience

December 8, 2016

Here are some highlights of the meeting that discussed in detail below, with links to the abstracts.

Progress on ANSWER ALS
ANSWER ALS is on track to be one of the biggest “precision medicine” initiative in ALS, through performing clinical, genetic, molecular and biochemical assessment on a proposed 1000 patient samples. All data will be shared with the larger research community to accelerate the search for understanding and new treatments even more. To date, the project has activated six clinical sites for recruitment and sample collection, and as of July had collected almost 200 samples. Induced pluripotent stem cells (iPSCs) are being made from each patient’s blood cells, and to date 21 lines have been created. Other aspects of the project, including genomics and proteomics analysis, are in the works.!/4071/presentation/3939

Update from NeuroLINCS
NeuroLINCS combines whole genome sequencing, epigenomics, robotic cell imaging, transcriptomics, and proteomics of 20 iPSC lines and derived motor neurons in the unperturbed state and in response to chemical perturbation. Researchers in the consortium presented the latest updates from the interlinked projects, including cell banking, analysis of resting and perturbed protein synthesis, and imaging of motor neurons. The findings will be used to better understand what unites and differentiates different types of ALS, and how best to develop therapies and track the response to them in cell culture.!/4071/presentation/3940!/4071/presentation/3942!/4071/presentation/3941

Watson Identifies New ALS-linked Proteins
ALS Association-funded Dr. Nadine Bakkar from the lab of Robert Bowser at Barrow Neurologic Institute in Phoenix, Arizona, described using IBM's Watson supercomputer to find new RNA binding proteins that may have relevance for ALS. RNA binding proteins are proteins that attach to RNA, the “working copy” of a gene that is used to make proteins. They have emerged as critical clues for understanding the ALS disease process, based on evidence that mutations in some RNA binding proteins cause some cases of ALS, and that interruption of their normal function may contribute to other cases.

For the search, the Watson supercomputer was first fed information about several RNA binding proteins with a known connection to ALS, including TDP-43 and FUS. Watson then “read” the entire scientific literature on RNA binding proteins, regardless of their known relevance to ALS, up to 2012, and constructed tree-like “concept maps” for each protein, mapping out the important functional relationships between each protein and its targets, associations and other data. Watson then compared the structure of each concept map to the ones it generated for the known ALS-linked proteins. Greater similarities in structure indicated higher likelihood of ALS relevance. With this, Watson identified 200 potentially relevant proteins, including several that were subsequently linked to ALS by standard research methods after the 2012 cutoff, confirming the validity of the approach. Next they expanded the literature analysis to 2015 and identified several new candidates that had not been found by other means. The team then looked in ALS tissue to determine which of the top candidates could be shown to be truly relevant for the disease. Among other discoveries, they found reduced levels of a protein called SYNCRIP, which functions in multiple steps of mRNA maturation and transport, and interacts with TDP-43, FUS, and SMN. These findings will help direct future work to understand the role of these new proteins in ALS, which may lead to a deeper understanding of the disease process and ultimately more targets for therapy.!/4071/presentation/6181

Understanding the Behavior of DPRs
The C9orf72 gene causes creation of unusual proteins called dipeptide repeats (DPRs). One such protein, called poly-proline-arginine (polyPR), is thought to be especially toxic, but the mechanism of toxicity is unknown. A research team from Belgium, including first author Steven Boeynaems of the University of Leuven in Belgium, showed that in a test tube, polyPR undergoes transitions in structure reminiscent of a chemical phase change from gas to liquid, forming droplets of concentrated protein from individual molecules. These droplets mimic the behavior of so-called stress granules, which form in cells under times of stress as a way to protect RNA molecules so that they can be used later for protein production. Results from the team suggest that polyPR's ability to form droplets may allow it to mix with stress granules and interfere with their function, pointing toward one possible mechanism of toxicity for this DPR.!/4071/presentation/6194

Nuclear Membrane Defects May be Common to Many Forms of ALS
Defects in the structure of the nuclear membrane have been found in cells carrying the C9orf72 gene mutation. Now, a research team from the lab of Wilfried Rossoll at Emory University in Atlanta, including first author Ching-Chieh Chou, has shown that nuclear membrane defects occur in ALS due to other causes, including TDP-43 mutation and sporadic disease. If replicated, the finding could strengthen the case that such defects unite many types of ALS, and contribute to the growing belief that disruption of transport in and out of the nucleus is a central problem in the disease. Understanding how the defects occur and how they can be mitigated will be important for developing treatments based on these findings.!/4071/presentation/8775

Ataxin-2 May Link Stress Granules to Nuclear Transport Defects
Work from Ke Zhang in the lab of Jeffrey Rothstein may link defects in nuclear transport and effects on stress granules in ALS. Dr. Zhang is a Milton Safenowitz Postdoctoral Fellowship recipient. The research team looked at the effects of small expansions in the ataxin-2 gene, an important genetic risk factor for ALS. Ataxin-2 is a component of stress granules. Overexpression of ataxin-2 leads it to bind with Ran, an important mediator of nuclear transport. The team found that when cells were subjected to stress, Ran ended up in stress granules, presumably interrupting nuclear transport. This seems to be a normal function of ataxin-2, possibly in order to limit protein-making activity in the face of acute stress. It is possible that this protective system is disrupted by mutations in ataxin-2, which may sequester Ran when it should not, thus altering nuclear transport in a harmful way. If this scenario is correct, it may explain how ataxin-2 mutations increase ALS risk, and strengthen the case for reducing the level of ataxin-2, such as through antisense therapy, as a treatment for ALS.!/4071/presentation/32844

Stress granules were also studied by Yousra Khalfalla of the University of Montreal, who showed that loss of TDP-43 protein, as occurs in many forms of ALS, leads to an acceleration of stress granule disassembly, which may be toxic.!/4071/presentation/32838

Mutant SOD1 Forms Strains that May Affect Transmission
When a misfolded protein clumps together, the resulting aggregate may take on a specific shape that can be identified with antibodies. Such reproducible shapes are called strains. In other neurodegenerative diseases, including Alzheimer's disease and prion diseases, different strains of the same protein are known to differ in important ways, including how rapidly the aggregate forms and how likely it is to move between cells and trigger spreading of aggregation. In ALS, SOD1 is known to aggregate, and some evidence indicates it can move between cells to spread disease. Here, a the research team from Sweden, including first author Thomas Brannstrom, showed that SOD1 aggregates display strain-like behavior, with different gene mutations leading to different strains. The results suggest that understanding strain-specific differences in ALS may lead to design of better anti-aggregate treatments.!/4071/presentation/31634

Protein Aggregation Inhibitor Protects Cells
Adrian Israelson of Ben Gurion University in Israel explored the importance of migratory inhibitory factor (MIF), a protein made by immune cells that inhibits the aggregation of mutant SOD1 protein, potentially beneficial in ALS due to SOD1 mutation, and possibly even beyond, since misfolded SOD1 occurs in other forms of the disease. The research team showed that absence of MIF accelerated disease onset in SOD1 mutant mice, and overexpression of MIF in cell culture protected cells against the effects of mutant SOD1.!/4071/presentation/32840

Novel Growth Factor Slows Disease Progression in ALS Mice
Cerebral dopamine neurotrophic factor (CDNF) is a novel growth factor that, like GDNF, promotes neuronal survival and thus may have therapeutic potential in ALS. A possible advantage of CDNF is that it diffuses through tissue better than GDNF, and thus may more easily spread throughout the nervous system. Francesca De Lorenzo of the University of Helsinki, Finland, showed that a single injection of CDNF into the central nervous system of SOD1 mutant mice soon after symptom onset slowed progression of disease, an effect that was more prominent in females than males, for unknown reasons. Further experiments are underway to determine the utility of this treatment for human therapy.!/4071/presentation/5385

Optimizing Brain-Computer Interface Technology
From the ALS Association-funded Simmons laboratory at Penn State College of Medicine in Hershey, Pennsylvania, Andrew Geronimo presented a poster focused on improving P300-based brain-computer interface (BCI) spellers. P300 is a brain wave that is active when the brain makes a choice, and thus can be used to detect the intent of someone making a choice with eye gaze on a spelling board, for instance. He found that using face stimuli during spelling tasks produced a unique response that may better serve patients with cognitive impairment. He also gave an update on his brain-computer interface study using telemedicine. His team achieved success with the first pair of patient-caregiver participants that learned to use BCI independently after multiple virtual telemedicine meetings. In January 2017, this study will be in full swing with numerous participants lined up to begin. Learn more about this study here and how to participate.!/4071/presentation/9375

A Mitochondrial Clean-up Protein Doesn’t Help in ALS
Parkin is a protein that tags mitochondria, the cell’s powerhouses, for destruction when they become damaged, and thus is essential for keeping cells functioning properly. Curiously, work from Giovani Manfredi and colleagues from the Weill Medical College of Cornell University in New York found that mice carrying the G93A-SOD1 mutation, which causes ALS, did better when parkin was eliminated, living longer and showing other signs of slower disease progression. This was despite the fact that mitochondrial damage is a prominent feature of ALS, and is thought to contribute to the disease. It may be that the presence of parkin worsens things by accelerating the loss of damaged but still functioning mitochondria, so that blocking parkin’s actions allows them to continue providing cellular energy for a bit longer.!/4071/presentation/31627

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