Research ALS Today Fall 2012

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ALS, FTD and New Discoveries in C9orf72 October 15, 2012 6:30 - 9:30 p.m. Hilton New Orleans Riverside Grand Ballroom C New Orleans, LA The ALS Association and The Association of Frontotemporal Degeneration are hosting an evening symposium at the Society for Neuroscience Annual Meeting

Does ALS Propagate? Safenowitz Fellowships Research Grant Program Lasker-Koshland Award Journal News

FALL 2012

Does ALS Propagate and Spread? by John M. Ravits, M.D.

Among the mysteries of ALS are its different looks from one patient to another. Each patient, it seems, has a different set of problems and challenges. Some are having trouble talking, some walking, some with their arms, some with their trunk. Now it is even being recognized that some patients have problems with language, behavior or even personality itself. One merely needs to go to a fundraiser, a support group, a meeting or a website to observe this. How can this be? How can one disease look so different from one person to the next? What is it that is common and allows the same diagnosis among people who seem so vastly different? The medical phrase for these apparent differences is phenotype heterogeneity. Phenotypes are the appearance of things. Heterogeneity is the difference. In ALS, phenotype heterogeneity includes the location of the weakness—for example, speech and swallowing (often called bulbar) or arms or legs—and the character of the weakness— upper motor neuron that creates stiffness and spasticity or lower motor neuron that creates limpness and atrophy or both. Underlying the appearance of weakness

is degeneration or disappearance of motor neurons in the central nervous system. The degeneration process somehow selects motor neurons above all other neurons for their target. Thus, what is common among patients is an underlying problem of degeneration of motor neurons, wherever in the central nervous system they may be located and whatever problems they may produce. The fundamental feature of ALS is motor neuron degeneration and resulting loss of motor function. So how does this explain phenotype heterogeneity? It turns out that motor neurons reside at specific anatomic locations in the brain, brainstem and spinal cord. Their location in the nervous system determines what muscles in what body region they control and the manner in which they control them. The motor system is thus a network of electrical circuits for the muscles. It took a titanic effort involving clinical neurologists, neuroanatomists, neuropathologists and neurophysiologists in Germany, Austria, Russia, England, Australia, Italy, Spain and France working more than 50 years in the second half of the 19th century to understand these wiring diagrams. And these discoveries took place at the same time ALS, a disease that

“...what is common among patients is an underlying problem of degeneration of motor neurons, wherever in the central nervous system they may be located and whatever problems they may produce.”

John M. Ravits, M.D. Professor of Clinical Neuroscience, Head ALS and Neuromuscular Translational Research University of California, San Diego

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Call for Research Abstracts - 6

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Milton Safenowitz Fellowships TREAT ALS™ Funds a Diverse Portfolio from Early Research, Drug Discovery to Clinical Studies It has been a year since the discovery of mutations in C9orf72, a landmark discovery for ALS research, which in some populations accounts for nearly 40 percent of familial and seven percent sporadic ALS. The past year has seen significant commitment to developing new model systems, understanding the human pathology and frequency of the mutation and beginning the development of therapeutic intervention strategies. With this comes an exponential growth in the number of investigators focused on ALS research. Not only does this mutation cause ALS, but it is also the major cause of frontotemporal dementia. Experts will come together at the international meeting of The Society of Neuroscience to discuss progress in C9orf72. In the meantime, efforts continue to understand the contribution of the other familial ALS genes––TDP-43 and FUS––and many new genes are emerging involved in sporadic and familial ALS. It is encouraging to see so many young scientists tackle many of these challenging projects and commit their time to ALS research. We are pleased to recognize the Milton Safenowitz Post-Doctoral fellows involved in a diverse array of exciting projects. Lucie Bruijn, Ph.D. Chief Scientist The ALS Association

ALS is a complex disorder. No one patient manifests the disease in exactly the same way. Dr. John Ravits and his colleagues have for many years questioned why this is so, and in this edition of Research ALS Today, he highlights this phenomenon and speculates the underlying causes. A better understanding of how disease spreads will guide therapeutic approaches. This is truly a promising time for ALS research with so many new avenues to explore and many treatment approaches underway. Without the dedication and commitment of scientists in academia and industry worldwide, we could not make significant progress for this devastating disease. With the increased collaboration and partnerships among the ALS organizations and researchers globally, significant progress has been made, and I am confident that meaningful therapies so desperately needed for this disease will become a reality. This edition highlights several new projects funded by The ALS Association, recent findings in the field reflecting the hard work of our dedicated ALS researchers, and encouraging new researchers to take up the challenge. -Lucie Bruijn, Ph.D.

The ALS Association is especially committed to bringing new concepts and methods into ALS research, and young scientists play an important role in this process. Funding is made possible by the generosity of the Safenowitz family through the Greater New York Chapter of The ALS Association, in memory of Milton, who died in 1998 of the disease. A drosophila model of the hexanucleotide repeats-induced toxicity in ALS Helene Tran, Ph.D. University of Massachusetts Medical School, Worcester, MA Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons. Unfortunately, there is no effective treatment. The etiology of ALS is complex, combining both environmental and genetic factors. Recently, two independent studies identified an abnormal (GGGGCC)n repeat expansion in a noncoding region of the C9orf72 gene in many cases of sporadic and familial ALS. To determine whether this repeat expansion contributes to the pathophysiology of ALS and to uncover the underlying disease pathways, the investigator proposes to develop a novel model organism expressing these repeats. The fruit fly is a powerful tool to elucidate these questions. Fundamental cellular processes related to neurobiology are highly conserved from flies to humans. In addition, flies have numerous advantages as an experimental model, including the ease of genetic manipulations, rapid propagation and short life spans. Therefore, establishing transgenic flies expressing this ALS/FTD-associated

(GGGGCC)n repeat expansion as a novel organism model of ALS will rapidly bring new insights into mechanistic questions and provide a valuable tool for evaluating prospective therapeutic strategies. “I am extremely honored and grateful to be a recipient of The Milton Safenowitz PostDoctoral Fellowship for ALS Research. With this encouraging support, I will establish in the Gao laboratory a new Drosophila model expressing the recently identified ALS/FTD-associated (GGGGCC)n repeat expansion. These novel transgenic flies will enable us to rapidly determine whether this genetic anomaly is pathogenic and will be valuable for uncovering mechanisms associated with the disease.”

Pathogenic role of wild-type superoxide dismutase in ALS Jacob Ayers, Ph.D. University of Florida, Gainesville, FL Mutations in superoxide dismutase 1 (SOD1) account for a major fraction of the inherited forms of ALS, and several studies have implicated its role in sporadic forms of the disease, which account for approximately 90 percent of all ALS cases. In this proposal, investigators aim to investigate the potential for normally folded, wild-type superoxide Continued on page 3


Safenowitz Fellowships Continued from page 2

dismutase 1 (SOD1) to adopt characteristics similar to mutant versions of the protein, including misfolding, formation of protein inclusions and toxicity. They intend to use various techniques to first induce a focal accumulation of mutant SOD1 in the spinal cord and then determine its effects on the properties of wild-type SOD1 and whether these effects can propagate throughout the central nervous system (CNS). Additionally, the investigators plan to study whether these changes in properties may occur through direct interactions between the two proteins and whether they are influenced by an inflammatory response within the CNS. The potential neurotoxic mechanisms examined in this proposal will not only be paramount in understanding the contributions of SOD1 in sporadic forms of ALS but may also have important therapeutic implications. “I am incredibly grateful to The ALS Association for its support of my research endeavors as I begin my studies in the ALS field. With its guidance and support, I am excited and optimistic that this project will help to shed light on the toxic mechanisms that occur during the course of this debilitating disease, and potentially highlight possible targets for therapeutic intervention.”

The role of VCP in regulating the assembly and disassembly of stress granules Regina Maria Kolaitis, Ph.D. St. Jude Children’s Research Hospital Memphis, TN Perturbed RNA metabolism is likely a major contributor to ALS pathogenesis. RNA-binding proteins (RBPs) are a major component of the pathological inclusions in most sporadic and familial ALS patients. Moreover, mutations in RBPs, TDP-43 and FUS/TLS, account for a small number of ALS cases. This study focuses on Valosin Containing Protein (VCP), a protein found in the pathological inclusions of ALS. Mutations in VCP cause a multisystem TDP43-opathy that includes motor neuron disease. Moreover, VCP mutations account for a small percentage of familial ALS cases. The investigators have recently discovered a role for VCP in regulating RNA metabolism and their evidence suggests that this role of VCP is compromised by disease-causing mutations. Prior members of the lab discovered genetic interaction between VCP and TDP-43 (and other RBPs). Subsequently, the investigators discovered physical interaction between VCP and TDP-43 (and other RBPs). Upon joining the lab, Dr. Kolaitis set out to elucidate the relationship between VCP and RBPs (including TDP-43 and FUS). During the past nine months, she has learned that VCP plays an essential role in the dynamics of a cytoplasmic ribonucleoprotein particle called a stress granule (SG). The investigator has established a dynamic imaging system that permits monitoring of SG assembly and disassembly. In preliminary studies, she has shown that

VCP is recruited to SGs and is essential for SG disassembly, including the liberation of TDP-43 from this structure. Moreover, ALS-causing mutations in VCP lead to impaired SG disassembly. This proposal is designed to test the hypothesis that VCP regulates the dynamics of SG disassembly, and this is the point of intersection with TDP-43 and FUS in ALS pathogenesis. “I am honored to receive The Milton Safenowitz Post-Doctoral Fellowship. My research goal is to elucidate how misregulation of RNA metabolism (especially translational control) leads to neurodegeneration in ALS, and how VCP is involved in this pathway. I believe the project supported by this fellowship will not only expand my research expertise in neurodegenerative diseases, but will also provide mechanistic insights into the pathogenesis of ALS, and I am hopeful that this could lead to new therapies.”

Disrupted microRNA biogenesis in ALS patient derived motor neurons Brandi-Davis Dusenbery, Ph.D. Harvard University, Stem Cell and Regenerative Medicine Cambridge, MA MicroRNAs are a recently discovered class of regulatory molecules that control diverse processes, including cell death. In particular, miRNAs are essential for the survival of motor neurons (MNs), the cell type which is lost in ALS. Interestingly, the protein machinery that makes microRNAs was found to associate with two proteins known to be disrupted in ALS, TDP-43 and FUS. This suggests that disruption of TDP-43/FUS may lead to alteration in microRNA production, which

may in turn lead to neurodegeneration. TDP-43 and FUS are expressed in many different cell types; however, MNs are selectively affected by their disruption. Thus, it is critical to study the function of TDP-43/FUS in MNs. Although several mouse models have been developed to study ALS, the results of these studies have failed to provide a significant clinical advance, perhaps because the underlying mechanism of MN loss in ALS is specific to human cells. The use of induced pluripotent stem cell (iPSC) technology allows skin cells from ALS patients to be converted into pluripotent cells, which can then be differentiated into large numbers of human MNs. The investigator proposes to use these cells to probe how TDP-43/ FUS regulate microRNA biogenesis and how their disruption leads to motor neuron disease. As microRNAs represent direct drugable targets, the identification and characterization of miRNAs disrupted in ALS could provide novel therapeutic opportunities. Moreover, these studies may allow the identification of a miRNA signature of ALS that could be utilized as biomarkers for diagnostic purposes. “I am extremely honored and grateful to receive The Milton Safenowitz PostDoctoral Fellowship for ALS Research. Support from the fellowship will allow me to pursue studies aimed to uncover the role of microRNAs in motor neuron disease. I am especially excited to examine the role of TDP-43– and FUS–regulated microRNAs in a cell type relevant to ALS, the human motor neuron. This will be achieved through the directed differentiation of ALS patient-derived induced pluripotent stem cells into motor neurons. As microRNAs represent direct drugable targets, I hope that understanding their regulation and function in motor neurons may provide novel therapeutic approaches for ALS.” Continued on page 5




Does ALS Propagate and Spread? Continued from page 1

attacks it, was being recognized and understood. Since the elucidation of these two–– the organization of the motor system and the disease that targeted it––happened at the same time, it was clear how they might be tied together. Recently, research by a number of neurologists in several countries has raised questions about this, pointing out that the two, in fact, might be integrally linked. Early in the disease of any one individual, before things become too complicated, clinical neurologists can surmise or impute by simple clinical examination where in the nervous system the failing motor neurons are located. They can localize where in the networks problems reside. Two striking features are now being increasingly discussed: (1) ALS begins very focally almost anywhere in the motor circuitry, maybe even randomly; and (2) ALS seems to progress outward from this location along anatomical pathways, either to the adjacent region or within specific networks. Remarkably, this implies that ALS spreads! It may be focal in the beginning, affecting discrete regions of the brain or spinal cord, but then it advances or moves outward anatomically in some manner by recruiting or capturing motor neurons in its immediate proximity. Thus, the phenotype heterogeneity that is so puzzling may be explained by (1) the specific site in the nervous system where it breaks out in the

beginning, and this may be random; (2) the degree to which the upper motor neuron and lower motor neuron are involved, and this is quite variable; and (3) the path of outward propagation, and this depends on its exact location. Ideas of spread have been discussed in the field of neurodegenerations for the past five or 10 years. Alzheimer’s disease and Parkinson’s disease, for example, are two degenerative diseases that share

with ALS the fact that certain populations of neurons are selectively vulnerable. In Alzheimer’s and Parkinson’s diseases, the concept of spread has been thought to occur in a stereotypical pattern from early to late in the disease. ALS, by comparison, because it appears to break out at a random location somewhere in the motor system, may be different, either because it is different or because this aspect of spread cannot easily be observed in the

A model of ALS progression based on focal onset and spread





Image courtesy of Ravits, J. M. et al. Neurology 2009;73:805-811

(A) Onset: At clinical onset, degeneration involves motor neurons in the brain and spinal cord that innervate the same peripheral body region (shown here as the innervation of the right hand). (B) Early spread: Over time, the disease process spreads through the brain and spinal cord and the clinical manifestations increase. (C) Continued outward spread: Over more time, the disease begins to become more complex. (D) Advanced spread: Ultimately, the disease process appears to be diffuse and symmetric, the details of which depend upon the onset.

other diseases. Are Parkinson’s disease and Alzheimer’s disease different in this regard? Or is it that ALS is giving us a unique window into neurodegeneration? These are parts of the puzzle currently being discussed and investigated. The immediate question to be answered in ALS is does this in fact occur and how orderly is it? Or are there other explanations, such as genetic or developmental programming, that could better explain the pattern of onset and progression for each patient. One clue is found in familial ALS (FALS). In FALS, a very specific gene defect causes the disease. This gene mutation is in every cell of the body, not just one location or one cell type. It is clear that there is marked phenotype heterogeneity within the family, probably similar to the heterogeneity that occurs in sporadic ALS. Some family members have bulbar disease, others begin in the arms and in others the leg and for the most part, the disease spreads outward. Thus, the genetic defect causes the disease to break out at a discrete anatomic location and this in turn determines the phenotype. How might spread occur at a cellular and molecular level? There are many different possibilities. One way is that the cellular microenvironment of the neurons gets corrupted in the disease and local changes induce a cascade of events that could propagate outward. A number of different cells are known to be involved in this, including astrocytes and microglia cells, Continued on page 5

1985: The ALS Association funds study of inherited motor neuron disease

TIMELINE 50s: DNA structure solved 1986: French neurologist Jean-Martin Charcot identifies ALS

50s: Nerve growth factor (NFG) identified–protective, growth promoting factor for nerve cells

1968: SOD1 enzyme identified

70s: Programmed cell death in motor neurons demonstrated

1986: Genes for muscular dystrophy identified

1990: Congress declares the 1990s the “Decade of the Brain”

1989: The ALS Association funds search for a common genetic link to ALS

1990: Growth factor CNTF is found to increase survival of motor neurons

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The ALS Association begins workshops Glutamate transporter shown to be defective in ALS 1991: Researchers link familial ALS to Chromosome 21

Growth factor BDNF found to increase survival of motor neurons




Does ALS Propagate and Spread? Continued from page 4

as well as the recent addition of oligodendrocytes, all cells that play vital functions separate from neurons. Another way that has emerged is that toxic soluble factor or factors may be diffusing through the nervous system, conjuring up a view of a toxic spill that is diffusing outward. And for many years important folding properties of proteins have been under intense study in what is called prion biology, the key property being that a protein can misfold and this misfolded protein can induce other copies to similarly misfold and thus spread in what is called prion-like propagation. Spread has important therapeutic implications! First, if we could understand the process of spread itself, we might be able to target this therapeutically; thereby, attacking the process that is attacking the cell. Second, if we could catch it early enough, we could combat it regionally. Drugs

permeate everywhere to reach the regions where they are needed. But regional strategies are different: they are local. The difference is similar to using a systemic antibiotic or a local salve to treat an infection. Nowhere is this difference more important than in current stem cell therapies. For a therapeutic fight to be waged by stem cells, they must be placed into strategic regions in the nervous system. They cannot be administered systemically. But what are “strategic regions”? Are they regions where the disease is most active? Alternatively, are they regions to where the pathology is advancing but not yet affected (in an effort to defend these while surrendering the others)? This will need to be defined as these therapies advance. During the next several years, disease spread will be increasingly studied and undoubtedly will lead us to new ideas, getting us even closer to the universal goal of a direct fundamental therapy to combat ALS.

Resources ALS mutations database

SOD1 mutant mice, Jackson Laboratory mouse models

Coriell NINDS DNA repository

Jackson Laboratories ALS Mouse Repository

ALS Epidemiology

Safenowitz Fellowships

Contribution of neurotensin to degeneration of vulnerable motor neurons in ALS Dimitry Yudin, Ph.D. Columbia University Medical Center, New York, NY Even in late-stage ALS patients, certain motor functions such as movement of the eyes and continence are preserved. This phenomenon is explained by the striking resistance to degeneration of the motor neurons that drive the corresponding muscles. If we could confer even part of that resistance on the motor neurons in the spinal cord that normally degenerate in ALS patients, we would have identified a strong new therapeutic strategy. One way of doing this is to identify genes that are selectively expressed in vulnerable spinal motor neurons and then to inactivate them either genetically or pharmacologically, starting in mouse models of ALS. The investigators recently showed that one gene expressed in vulnerable motor neurons is neurotensin, a 13-amino acid peptide whose role has never been studied in the neuromuscular system. However, it has multiple properties that suggest it might contribute to neurodegeneration. Neurotensin reinforces excitotoxicity in models of Parkinson’s disease, contributes to neurodegeneration in stroke and activates inflammatory processes in the brain. The investigator therefore proposes that neurotensin may contribute to motor neuron degeneration and neuroinflammation in ALS. He will test this first by studying the precise subset of motor neurons in which neurotensin and its receptors are expressed. Next, he will ask whether inactivation of neurotensin in mutant SOD1 mice, the most frequently studied model of ALS, delays muscle paralysis and prolongs lifespan. Lastly, he will ask whether neurotensin makes mouse and human motor neurons more vulnerable to disease-related stressors. Thus this study should uncover new details of the disease mechanism in ALS and, hopefully, will help identify a new therapeutic target in this currently incurable disease. “The Milton Safenowitz Fellowship will allow me to pursue my studies of the selective resistance of certain motor neurons to ALS. I hope that this will allow me to identify new therapeutic targets that will be of help to patients in the future.”

Control and SOD1 fibroblasts

SOD1 mutant rats, Taconic http://www. ALS Untangled ALS Association Research Webinars

TIMELINE cont. SOD1 gene mutation (chromosome 21) discovered in familial ALS Trials using glutamate blocker riluzole begin

The ALS Association co-sponsors workshop on high-throughput drug screening with NINDS

Animal studies combining CNTF and BDNF demonstrate decreased motor neuron loss GDNF rescues degenerating motor neurons during development in an in vitro experiment

FDA approves riluzole

Toxic properties of the SOD1 enzyme discovered and linked to familial ALS

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RNAi discovered by Craig Mello and Andrew Fire

NINDS issues first ever RFA (request for applications) specifically for ALS research

A transgenic rat is designed; efforts start on fly model

The ALS Association holds scientific workshop on “Environmental Factors and Genetic Susceptibility”

Attention turns to support cells of nerve tissue to find role in ALS

Aggressive search for new ALS genes funded by The ALS Association

Inflammation and programmed cell death gather research interest

Scientists complete map of mouse genome

ALS2 gene (alsin protein) linked to juvenile ALS

Agency of Toxic Substances and Disease Registries awards five grants focused on ALS

The ALS Association/NINDS collaborative effort begins screening drugs

Department of Defense approves funding for ALS-specific research

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Call for Research Abstracts Due January 2013 The ALS Association Research INVESTIGATOR-INITIATED RESEARCH GRANT PROGRAM supports INNOVATIVE research of high scientific merit and relevance to amyotrophic lateral sclerosis (ALS), offering investigators awards in the following categories:

Multi-year Grants: The ALS Association will support research that is projected for periods of up to three (3) years. Funding for multiyear grants is committed for one (1) year only, with noncompetitive renewals conditioned upon results. These applications require strong preliminary data. Awards will be in the amount of up to $80,000 per year. Starter Grants: One-year awards for NEW INVESTIGATORS ENTERING THE FIELD OF ALS. Alternatively, they can be PILOT STUDIES BY ALS INVESTIGATORS. These applications do not require strong preliminary data but must emphasize innovation, scientific merit, feasibility and relevance to ALS. The maximum amount awarded is $40,000. The Milton Safenowitz Post-Doctoral Fellowship for ALS Research Awards: The maximum amount awarded is $50,000 per year for two (2) years. Eligibility is limited to those who have been a fellow for one year or less. Request an abstract form for any of these categories from You will be notified within two weeks of the abstract submission due date whether you are eligible to submit a full application. See schedule below.

Grant Schedule

Call for Abstracts December 3, 2012 Abstracts Due January 14, 2013 Full Application Due March 1, 2013 Award Announcements July 2013 Funding Commences August 1, 2013

TIMELINE cont. Study shows surrounding support cells play key role in ALS Study shows that human embryonic stem cells can be stimulated to produce motor neurons Gulf War study shows that vets deployed to Persian Gulf in 1991 developed ALS at twice the rate of those not deployed there IGF-1 gene therapy study proves beneficial in mice with ALS VEGF gene abnormalities shown to be potential factor in ALS The ALS Association collaborates with U.S. Department of Veterans Affairs to enroll all vets with ALS in registry Early tests of ceftriaxone appear to increase survival in mice with ALS Combination of creatine and minocycline prove more effective together in mouse model than either drug alone


New TREAT-ALS Grants Attack the Disease on All Fronts ™

The ALS Association’s TREAT ALS™ program focuses on understanding new genes, new disease models, new pathogenic hypotheses and new therapeutic strategies. New grants, totaling more than $4 million, go to 31 labs in five countries. TREAT ALS™ (Translational Research Advancing Therapies for ALS) is focused on building the tools, infrastructure and partnerships designed to speed development of treatments for ALS. Understanding New Genes RNA metabolism has emerged as a potentially major theme in ALS. Two new genes—TDP-43 and FUS— encode RNA-binding proteins, angiogenin is an RNA processing protein, and the ALS-causing mutation in the C9orf72 gene creates large quantities of excess RNA, which researchers suspect may contribute to disease. Newly funded studies will explore both the normal functions and consequences of mutation in these genes. • Researchers will examine the interaction of TDP-43 with microRNAs in skeletal muscle, an interaction which may be disrupted in ALS and which may affect formation of the neuromuscular junction. • TDP-43 is also capable of counteracting retroviral replication, which may help protect motor neurons. Researchers will determine whether this activity plays a role in healthy neurons, and is disrupted by ALScausing mutations. • TDP-43 is mislocalized in ALS, from the nucleus to the cytoplasm. Investigators have identified a nuclear localization factor that interacts with TDP-43, and will explore how their interaction is altered in the disease. • TDP-43 and FUS may work together in common Study implicates smoking as likely risk factor in sporadic ALS Study releases evidence that mitochondrial malfunction may play an important role in ALS Study funded by The ALS Association to find biomarkers in cerebrospinal fluid and blood

pathways, including one that affects the transcription factor NF-kB. By better characterizing these effects, researchers hope to gain insights about new pathways for therapy development. • Researchers will characterize the role of angiogenin in stress-induced cell responses, and explore the consequences of ALS-causing angiogenin mutations. • The basic biology of the C9orf72 gene in both normal and mutated forms will be the target of several new studies, as researchers attempt to discover the pathways affected by this new and important ALS gene. These studies include generating new cell, fly and worm models and examining the gene’s behavior in patient tissues. Building New Disease Models The SOD1 mouse has long served as the standard model for ALS disease research. But the discovery of new disease genes and development of new stem cell techniques have provided extraordinary new opportunities to build new models and ask new questions about the disease. Among the most promising new techniques is induced pluripotent stem cells (iPSC), derived from a patient’s own tissues. Working in vitro, researchers can induce skin fibroblasts to differentiate into stem cells, and then re-program them into any type of cell, including motor neurons and skeletal muscle. This then provides an abundant source of cells that can be studied to understand their vulnerabilities. They also provide a source of ALS-linked cells for high-throughput drug screening. New grants will help develop iPSC for both of these strategies. Researchers will examine whether motor neurons are hyperexcitable in ALS, and

Ceftriaxone increases levels of the glutamate transporter GLT1 in a mouse model of ALS First international workshop on frontotemporal dementia discusses link to ALS Stem cells engineered to make GDNF survive when transplanted into rats modeling ALS Early data suggests that mutant SOD1 may be secreted by and may activate microglia Launch of TREAT ALS initiative (Translational Research Advancing Therapies for ALS) to accelerate clinical trials in ALS VEGF increases survival in a rat model of ALS while improving motor performance

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ALS patient samples collected to NINDS ALS Repository Repository samples allow genome analysis for sporadic ALS First TREAT ALS clinical trials funded First TREAT ALS clinical trials begun TDP-43 discovered as a common link in FTD, ALS Chromosome 9 region intense focus for FTD

Stem cell study shows SOD1 mutant support cells can kill any motor neuron ALS U.S. registry efforts gaining ground in Congress Fish model of ALS: Progress reported SOD1 in altered form common to both sporadic and inherited ALS Engineered stem cells making GDNF help motor neurons survive in SOD1 mutant rats First genome screening data published based on NINDS ALS Repository

2003 2004 2005 2006 2007


New TREAT-ALS Grants ™

Continued from page 6

whether neuromuscular junction formation is impaired in ALS skeletal muscle. Investigators will also use existing progenitor cells from the brain to study the development and function of corticospinal motor neurons, and to better determine how they may be controlled to direct them to grow to their final targets. The nematode Caenorhabditis elegans will be used to study the basic biology of the C9orf72 gene. This transparent, short-lived worm is ideal for rapidly identifying potential pathways affected by gene mutations, since much of its cellular biology is understood at the genetic level. Similarly, the zebrafish provides a good vertebrate model for understanding the consequences of gene mutations, since it, too, is transparent and has a short lifespan. One group of researchers will use the zebrafish model to examine the role of SOD1 in altering excitation-induced calcium signaling, which can lead to cell death. Another group will use the zebrafish to explore the ephrin guidance system in the developing and regenerating nervous system. They have previously found that deletion of a receptor in this system is protective in the fish model of ALS.

new therapies. New research seeks to better characterize some familiar pathways, takes aim at several newly recognized ones, and attempts to determine the potential involvement of novel ones. • Neuroinflammation will be rigorously explored in the SOD1 mouse to better characterize the proinflammatory factors at work, which may exacerbate disease. • The newly discovered ALS gene ubiquilin-2 will be examined in a mouse model to understand its role in dysregulation of protein degradation in ALS. A related gene is known to play a role in Alzheimer’s disease. • A signaling pathway called Wnt regulates the survival of axons in motor neurons, and in SOD1 mice, this pathway appears to be dysregulated. Investigators will explore this system further to determine how it functions, and whether it may provide a target for new treatments. • The potential role of spinal interneurons will be investigated to determine if these degenerate in ALS, and whether they may be a potential therapeutic target.

Researchers will also take advantage of fly and cell culture models to explore the aggregation of TDP-43, a hallmark of most forms of ALS. These same models will serve as high-throughput screens for drug discovery aimed at reducing aggregation, which may be therapeutic.

• Environmental toxins have long thought to contribute to some cases of ALS. Two in particular, BMAA and methylmercury, have been proposed to be linked to ALS, and are found in fresh waters in the Northeast and elsewhere. Researchers will compare toxin distribution to the distribution of ALS cases to begin to explore whether there is a connection between the two.

Exploring New Disease Pathways

New Strategies for Treatment

It is likely that there are several different pathways that cause motor neuron degeneration, and understanding how these act, and interact, is central to developing


Much has been learned about the vulnerabilities of motor neurons in the past two decades. It is clear that neurons of all types require trophic support, in the form of neurotrophic factors such as GDNF, and some attempts have been made to deliver GDNF to patients with neurodegenerative disease. How that support is delivered may be crucial to its potential for success. GDNF can be delivered either genetically, through viruses carrying the gene, or with implanted stem cells

Stem cells generated from ALS patients Discovery of DPP6 in two genome-wide association studies in ALS Mutations in TDP-43 linked to familial and sporadic ALS Induced Pluripotent Stem Cell Technology opens up new avenues for ALS

Identification of new gene linked to familial ALS, Fused in Sarcoma (FUS) on Chromosome 16 FDA approval of SOD1 antisense and stem cell trials in U.S.

First patients enrolled for antisense and stem cell trials in U.S.

Ubiquilin-2 discovery; C9orf72 discovery

March: The ALS Association hosts 2nd Drug Discovery Workshop for ALS September: Researchers find genetic region influencing age at which people develop ALS






that act as “mini-pumps” to generate and secrete GDNF. Researchers will investigate whether combining these two approaches in the SOD1 rat model can ameliorate the disease. If successful, this approach may be a promising therapeutic strategy in patients. Another two-pronged strategy will be tested by another group. Their goal is to deliver growth factors and to reduce SOD1 expression, both accomplished by viral delivery of genes into the central nervous system. Success in the animal model may provide the rationale for treatment in ALS patients. “The breadth of our newly funded projects attests to the interest and commitment of researchers throughout the world to understand ALS and find treatments based on that understanding,” said ALS Chief Scientist Lucie Bruijn, Ph.D. For more information about The ALS Association research program visit the website at

ALS Association Research Scientific Advisory Board Chair Receives Distinguished Award Tom Maniatis, Ph.D., Biochemistry and Molecular Biophysics Department Chair at Columbia University Medical Center, received the 2012 Lasker-Koshland Special Achievement Award in Medical Science. Dr. Maniatis has been instrumental in helping The Association shape its Translational Research Advancing Therapies for ALS (TREAT ALS TM) program, through which The Association funds a diverse portfolio of research to find treatments and a cure for Lou Gehrig’s Disease. In addition, The ALS Association Greater New York Chapter will honor Dr. Maniatis with the 2012 Jacob K. Javits Lifetime Achievement Award.




J OU R N A L N E W S Age of Onset Locus Discovered on Chromosome 1 An international consortium of researchers convened by and funded in part by The ALS Association has identified a region on chromosome 1 that strongly influences the age of onset of ALS. The study examined DNA from more than 4,000 ALS patients and 5,000 controls of Caucasian origin from centers in the United States and Europe, including Belgium, France, the Netherlands, Ireland, Italy, Sweden and the United Kingdom. The study was conducted by The International Consortium on Amyotrophic Lateral Sclerosis Genetics (ALSGEN). The strongest association with age of onset was within 1p34.1, a region harboring multiple genes. Individuals with a specific single nucleotide polymorphism (SNP) marker had an age of onset approximately two-and-one-half years earlier than those without it (average age at onset approximately 56.5 years versus approximately 59 years). In addition, the study, published in the journal The Neurobiology of Aging, confirmed known genetic risks for ALS and suggested novel regions that merit more study. Of potential significance is that the locus appears to influence age of onset independent of the underlying cause of ALS, and thus may reveal a mechanism common to multiple ALS etiologies. “Although much work remains to unravel the mechanism or pathway involved in the chromosome 1 locus,” the authors write, “this may represent the first identification of a component of the final common pathway of motor neuron degeneration.”

Axonal Guidance Gene Linked to ALS A gene involved in axonal guidance modifies age of onset and survival in ALS, according to a study published in Nature Medicine. The gene, called EPHA4, encodes a receptor in the ephrin axonal repellent system, which helps guide spinal motor neurons to their targets. The researchers, led by Wim Robberecht of the University of Leuven, Belgium, found that blocking expression of the gene protected motor neurons from the harmful effects of mutant SOD1 in multiple animal models. In SOD1 rats, pharmacological blockade of the receptor delayed disease onset and prolonged survival. In the TDP-43 mutant mouse model of ALS, either genetic or pharmacologic reduction of receptor signaling mitigated phenotypic abnormalities. Reduction of signaling also improved the phenotype of a fish model of spinal muscular atrophy, a distinct motor neuron disease, suggesting “the ephrin system may be a generic determinant of vulnerability of neurons to degeneration,” the authors state. The importance of the gene for ALS in humans was confirmed through a genetic association study in nearly 3,000 ALS patients. Lower expression of EPHA4 was associated with later disease onset and longer survival.

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C9orf72 Hexanucleotide Repeat Expansions in Patients with ALS from the Coriell Cell Repository Investigators report the frequency of this new mutation and its associated clinical phenotypes in a cohort of patients obtained from the Coriell Cell Repository. These samples were collected as part of a large collaboration with The ALS Association,

NINDS, MDA and the ALSRG and provide an important resource for researchers globally. The sample analysis in the current study was led by Rosa Rademakers of Mayo Clinic-Jacksonville. As reported in Neurology, of the 617 samples analyzed, 11.8 percent carry the pathogenic repeat expansion, including 37 percent of familial ALS cases and 4.9 percent of sporadic cases.

Progress in Understanding TDP-43 Biology Mutations in the TDP-43 gene are a rare cause of ALS, but TDP-43 protein is found in cytoplasmic aggregates in almost every form of ALS. Thus, understanding the basic cell functions of TDP-43, and how it goes awry in ALS, may potentially provide insight into the causes of the disease. A key feature of normal TDP-43 is that it shuttles between nucleus and cytoplasm. A new study in Human Molecular Genetics identifies an endoplasmic reticulum calcium channel, called type 1 inositol-1,4,5-trisphosphate receptor (ITPR1), as central to the movement of TDP-43. Inhibition of ITPR1 increased clearance of TDP-43 through the autophagosome pathway, suggesting that ITPR1 inhibition may represent a promising drug target for preventing accumulation of TDP-43.

Blood Biomarker for Early Disease Implicates Immune System SOD1 mice and ALS patients have increased levels of inflammatory monocytes in the peripheral circulation early in the disease, and their detection may provide a biomarker for early disease progression, according to a new study by Howard Weiner of Harvard Medical School and colleagues. The study, funded in part by The ALS Association and published in The Journal of Clinical Investigation, also shows that blocking the inflammatory molecules with antibody was therapeutic in the SOD1 mouse, suggesting a potential new avenue for therapy.

Patient-Derived iPSC for ALS Drug Screening Induced pluripotent stem cells (iPSC) are generated from skin fibroblasts, and can be differentiated into any cell type, including motor neurons. In Science Translational Medicine, Haruhisa Inoue and colleagues from the Center for iPS Cell Research and Application, Kyoto, Japan, report developing iPS cell-derived motor neurons from patients carrying TDP-43 mutations, which manifest several key features of human disease, including protein aggregates and shorter neurites. They also report initial drug screening results suggesting that a histone acetyltransferase inhibitor called anacardic acid may be a promising compound for therapeutic development.

Challenges of Neural Stem Cell Replacement Therapy A transplantation study in SOD1 rats highlights the difficulties of developing stem cell transplantation as a therapy for ALS. Transplantation of human fetal spinal neural stem cells led to only local protection and transient improvement, with no effect on motor neurons distant from the transplant site. In particular, descending motor axons continued to degenerate despite treatment, indicating that multi-level treatment may be required to gain a therapeutic effect. The study, led by Martin Marsala at the University of California in San Diego, was published in PLOS One.

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