Skip Navigation

Completed Projects

flower close-up

The following research grants have concluded:

Philip Wong, PhD
Functional role of the C-terminal prion-like domain of TDP-43

Zuoshang Xu, PhD & John Landers, PhD
Modeling ALS in mice based on profilin 1 mutation

Timothy Miller, MD, PhD
miRNA enriched in ALS-vulnerable motor neurons as therpeutic targetsThe following research grants have concluded:

Aaron Gitler, PhD & James Shorter, PhD
Genetic and biochemical approaches to define mechanisms of RAN translation in C9orf72-associated ALS

Terry Heiman-Patterson, MD
Phenotype modifiers in murine motor neuron disease: studies in the G93AhSOD1 mouse models of ALS

Jean-Pierre Julien, PhD
Single-chain antibodies against TDP-43 RRM1 domain for treatments of ALS

Edor Kabashi, PhD
Functionally characterizing genetic interactions between ATX2 polyQ repeats and TDP-43

David Borchelt, PhD & Jacob Ayers, PhD
Role of misfolded wild-type SOD1 in cases of sporadic ALS

Wim Robberecht, MD, PhD
University of Leuven, Belgium
Role of Oligodendrocytes in the Pathogenesis of Mutant TDP-43 Associated ALS

Oligodendrocytes have recently been shown to contribute to the pathogenesis of ALS. TDP-43 plays a role both in familial and sporadic ALS. In this project, we intend to investigate whether expression of mutant or wild-type TDP-43 in oligodendrocytes or in oligodendrocyte precursor cells is sufficient to cause motor neuron degeneration. We also intend to compare the potential motor neuron degeneration in oligodendrocytes to the phenotype induced by selective expression of mutant or wild-type TDP-43 in motor neurons.

Laura Ranum, PhD
Univeristy of Florida
Molecular Genetics of the G4C2 expansion mutation in ALS/FTD

A novel form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) was recently shown to be caused by a DNA mutation in which six letters of the genetic code “GGGGCC” are repeated extra times. This discovery links ALS/FTD with a large group of other neurological diseases caused by similar repeat expansion mutations (e.g. CAG, CTG, CCTG), which is particularly exciting because lessons learned over the past 20 years from studying these other diseases are likely to be relevant to the more common ALS/FTD. My laboratory has followed a family with ALS for more than 20 years and recently discovered that this family has the GGGGCC expansion mutation. We have cloned the repeat expansion mutation from a member of this family and propose a series of experiments, including the generation of a mouse model to better understand how this expansion mutation causes disease.

John Landers, PhD & Feb-Biao Gao, PhD
University of Massachusetts
Modeling ALS-Associated Cytoskeletal Mutations in iPSC and Drosophila

The cytoskeleton is the scaffolding that helps the cell maintain its shape. Recently, we determined that mutations in two cytoskeletal proteins cause ALS. Here, we propose to introduce these mutations into induced pluripotent stem cell-derived human neurons and Drosophila to study how they contribute to the development of ALS.

Jared Sterneckert, PhD
Dresden University of Technology
Identification using HTS of small molecules protecting iPSC-derived MNs with mutant C9orf72 against degeneration

Patients with amyotrophic lateral sclerosis (ALS) become progressively paralyzed because their motor neurons (MNs) degenerate. Mutations in the gene C9orf72 are the most common known genetic cause of ALS. Reprogramming enables us to create stem cells directly from patients with mutations in C9orf72, which can be used to replay ALS pathology in a dish. Because it is stem cell-based, we can replay this model thousands of times and test new drug-like compounds for their ability to prevent ALS. As part of this project, we aim to test about 50,000 new drug-like compounds to identify new hit compounds, which, in the future, we hope to develop into new drugs that can prevent paralysis in patients with ALS.

Note: Funding for this project is made possible by Ann Arbor Active Against ALS (A2A3).

Philip C. Wong, PhD
Johns Hopkins University
Determining the pathogenic mechanism(s) of C9ORF72-linked ALS-FTD
Funding for this project was made possible through a collaboration between the Packard Center and ALSA; Packard Center funding made possible by A Midwinter Night's Dream

The hexanucleotide GGGGCC repeat expansion in a gene termed C9ORF72 is the major cause of ALS and FTD, but how such expansion causes malfunction of nerve cells in these illnesses remains unknown. We plan initially to develop mouse model systems to test if losing the activity of C9ORF72 is responsible for death of motor neurons and secondly, whether toxicity arises through the presence of a toxic RNA derived from the diseased C9ORF72 gene that determines malfunction of motor nerve cells. Outcomes from studies proposed in this application will clarify how the repeat expansion in the C9ORF72 gene causes motor nerve cell loss in a large proportion of cases of ALS. These efforts will have important implications for design of therapy and provide useful mouse model systems for testing therapies that would eventually benefit patients with ALS.

Philip C. Wong, PhD
Johns Hopkins School of Medicine
Generation and Characterization of Wildtype and ALS-linked FUS/TLS mice
Funding for this project was made possible by the Muscular Dystrophy Association

The discovery of mutations in a gene encoding an RNA binding protein (FUS/TLS) linked to both sporadic and familial ALS provides the opportunity to further our understanding of the underlying cause of this illness. In this proposal, we plan to study the effects of an ALS-associated mutant FUS/TLS protein in transgenic mice and identify any resulting motor neuron disease. If disease results, this mouse model will help clarify the behavioral and pathological signs associated with ALS onset and disease progression. These transgenic mice will also help with the design of therapeutic strategies to attenuate this devastating disease.

Zuoshang Xu, PhD
University of Massachusetts
Modeling ALS by TDP-43 hypomorphism in mice

TDP-43 is a key causal gene that is involved in a majority of ALS cases, including the sporadic and some familial cases. To understand the role of TDP-43 in neurodegeneration and to design therapeutic strategies, a critical question to resolve is whether TDP-43 causes neurodegeneration by a gain of toxicity, e.g. from forming toxic protein aggregates, or from loss of its function, e.g. from mutations or being absorbed into the aggregates. To answer this question, both overexpression and loss-of-function models are necessary. This proposal will establish a transgenic mouse model for ALS by decreasing the level of TDP-43. This model will be important for understanding the disease mechanism and designing therapeutic strategies.

Udai Pandey, PhD
University of Pittsburgh
A Drosophila Model to Investigate the Role of FUS in ALS

ALS is marked by abnormal accumulations of a protein named FUS/TLS. In creating fruit flies (Drosophila melanogaster) that carry the human FUS/TLS gene, we've found an economical, easily-studied model of ALS. Our goal with this Packard grant is to understand how the FUS/TLS gene promotes the disease in Drosophila. What we discover, we assume, will shed clearer light on both familial and sporadic ALS in patients.

Don Cleveland, PhD
Ludwig Institute for Cancer Research/UCSD
Mice expressing C9orf72 RNA for antisense oligonucleotide therapy development and decoding disease mechanism
Funding for this project was made possible through a collaboration between the Packard Center and ALSA

The most frequent cause of inherited ALS was discovered in October 2011 to be a large expansion of a hexanucleotide repeat in the C9ORF72 gene. When that large repeat is copied into the messenger RNA which carries the information encoded by the gene, the mRNA aberrantly accumulates. In other diseases caused by expanded repeats like myotonic dysrophy, factors required for processing the mRNA with the expansion – and needed for processing RNAs encoded by other genes – get trapped on the expanded repeat sequence, and correspondingly fail to mediate processing of the other RNAs. Building on that example and in partnership with Isis Pharmaceuticals, we have designed a gene silencing approach to develop a drug - called an antisense oligonucleotide or ASO - that will selectively destroy the ALS-causing mRNA with the expanded repeat. . We will build a mouse model expressing the expanded human C9ORF72 mRNA and use this to validate the efficacy of the ASO drug in development. The mice may also represent models that will develop ALS-like disease and which can be used to determine exactly what goes wrong in the presence of the aberrant mRNA.

Solange Brown, MD, PhD
Johns Hopkins University
Inhibitory Cortical Circuits in Presymptomatic ALS

One of the hallmarks of ALS is the death of upper motor neurons in the cerebral cortex. However, it is not known whether more subtle changes in cortical circuits precede upper motor neuron degeneration. We propose to study the excitatory and inhibitory neurons of the motor cortex, and their patterns of connectivity, to determine whether functional changes in these circuits represent early events in the development of the disease. The goal of this work is to identify primary events in the disease process that can suggest new preventative strategies and therapeutic targets in ALS. Furthermore, combining this work with the studies of lower motor neurons will give a fuller picture of why motor neurons are particularly vulnerable in ALS.

Yongjie Yang, PhD
Tufts University
Role of Astrocyte Exocytosis in the Pathogenesis of ALS

This project aims to investigate the role of chemicals secreted by astrocytes in pathogenesis of motor neuron degeneration by employing novel mouse genetic tools. Results from this study will demonstrate whether these secreted compounds contribute to toxicity in astrocytes with a mutation in SOD1 and provide clues how to identify the toxic factors from astrocytes. Ultimately these results will help develop astrocyte-based neuroprotective strategies against motor neuron degeneration in ALS.

Brian Kaspar, PhD & Dwight Bergles, PhD
Nationwide Children's Hospital & Johns Hopkins
Development of Gene Delivery to Oligodendrocytes
Funding for this project was made possible through a collaboration with P2ALS and ALSA

Inherited forms of amyotrophic lateral sclerosis (ALS) have been linked to mutations in genes that are widely expressed by both neurons and their supporting glial cells. In mouse models of ALS, deletion of mutant genes from glial cells can significantly prolong life, indicating that these non-neuronal cells are important contributors to this disease. Our recent studies in G93A SOD1 mice show that oligodendrocytes, a class of glia that form myelin sheaths around axons, degenerate in the spinal cord, and that selective removal of mutant SOD1 from oligodendrocytes prolongs life. These studies indicate that oligodendrocytes are an important target for therapeutic manipulation in vivo. Although it is possible to manipulate gene expression in oligodendrocytes in mice using complex transgenic manipulation, such approaches are not applicable for therapeutic intervention in humans. We intend to use a new technique known as molecular or directed evolution to engineer an adeno-associated virus (AAV) that will readily infect oligodendrocytes but not other cells. Generation of this vector will help define the mechanisms responsible for oligodendrocyte degeneration in ALS, and enable development of new strategies to minimize the toxic effects of these mutant proteins in vivo.

Giovanni Manfredi, MD, PhD
Weill Medical College, Cornell University
Mitochondrial involvement in TDP-43 mutant mice

Mitochondria provide neurons with the energy necessary for their function and survival. In ALS, mitochondria degenerate, and fail to provide adequate energy supplies to cells, thereby participating to their death. Our current knowledge on mitochondrial dysfunction in ALS is mostly limited to familial forms of the disease with SOD1 mutations, but new evidence links mitochondrial abnormalities with another form of familial ALS associated with TDP-43 mutations. In this application, we propose to apply our expertise on mitochondrial biology to understanding how mitochondrial dysfunction is involved in the disease, in a TDP-43 transgenic mouse model. We will characterize the bioenergetics and dynamics of neuronal mitochondria and their ability to control the levels of calcium, a fundamental ion that regulates vital cellular functions.

Aaron Gitler, PhD
University of Pennsylvania
Novel Yeast and Zebrafish Models to Explore the Role of FUS/TLS in ALS

In motor neurons of both humans and many animal models of ALS, it's not uncommon to find abnormal clumps, or aggregations, of several proteins. Gitler and Granato propose to study the biology of one of them, a protein that's generated by the FUS/TLS gene. Using yeast cells as easy-to-study model systems, they hope to learn how and why the FUS/TLS protein forms clump within cells and how that's related to motor neuron death. Other work involves studying FUS/TLS in zebrafish, which are both fast-dividing and transparent, enabling easy study.

Jean-Pierre Julien, PhD
Laval University, Quebec
Intrabody-based therapy for blocking TDP-43 interaction with NF-?B p65

We recently discovered that an upregulation of TDP-43 in ALS acts as co-activator of nuclear factor-?B (NF-?B), which can induce hyperactivity of NF-?B resulting in exaggerated innate immune responses and increased neuronal vulnerability to toxic environment. Here we propose to develop a therapeutic approach that uses intracellular antibodies (intrabodies) that work in the nucleus to block the specific interaction between TDP-43 and a small piece of NF-?B known as p65. First, we will use a hybrid of two different cell culture lines to generate monoclonal antibodies against the N-terminal domain and RRM1 domains of TDP-43. Then, from the appropriate hybrid cell lines we will derive small pieces of DNA to generate intrabodies using an adeno-associated virus to block TDP-43 and p65 interaction in the nucleus, thereby alleviating ALS.

Mohamed H. Farah, PhD
Johns Hopkins University
New tools for the assessment of pathology and therapeutic responses in models of motor neuron diseases

This renewal project will continue the work of Packard scientist Dr. John W. (Jack) Griffin, who passed away untimely earlier this year. Dr. Griffin identified the lateral thoracic nerve/cutaneus maximus muscle (LTN/CMM; Griffin et al., 2010) as a system that has unique advantages for visualization and electrophysiological analyses of motor nerve and neuromuscular junction degeneration. We propose to carry out detailed morphological studies and electrophysiological analysis of the LTN/CMM system in a G93A SOD1 mouse at early stages of axon terminal degeneration. The goal is to thoroughly characterize the CMM/LTN system in SOD1 mouse model and identify the earliest degenerative events in order for the method to be widely adopted in future studies to aid in much higher throughput of pathogenetic analysis and therapy development in the field.

Don Cleveland, PhD
Ludwig Institute for Cancer Research/UCSD
Transcriptome analyses on tissue from C9orf72 ALS patients

Funding for this project was made possible through a collaboration with Packard Center, Project ALS and P2ALS

We propose to use RNA sequencing approaches to determine whether expression of the C9orf72 expansion affects the RNAs within lumbar spinal cord in comparison to parallel analyses of normal spinal cords. We will identify (using DNA blotting) the length of the expansions in each of the three c9orf72 casesand determine whether there is a clear C9orf72 signature. Our RNA expression analysis will be done much as we have already done for RNAs from normal cells and tissues or those depleted of TDP-43 (Polymenidou et al, Nat. Neurosci. 2011). If C9orf72 signatures RNA signatures are identified, we would propose to extend this analysis to RNAs from the cortex and from cerebellum.

Bryan Traynor, MD
National Institute on Aging, NIH
ALS gene discovery using exome sequencing

This Packard grant was awarded to employ a new technique, exome sequencing, to find the single, mutant genes that underlie familial ALS. These familial genes will also be be screened in the commoner sporadic form of disease. The overall result, then, will be identification of genes underlying ALS.

The technique centers on ultra-new technology that can rapidly sequence DNA, and directing it to single out those areas of the human genome that code for proteins. (This key part is called the exome and makes up about 1 percent of the human genome.) Within three months of obtaining funding, we should be able to fully sequence 21 exomes. The sequence data we derive from this project will be made available on a public website, offering a much-awaited resource for ALS researchers worldwide.

Catherina Becker, PhD
University of Edinburgh
Generation and Integration of New Motor Neurons in the Adult Spinal Cord of Zebrafish  
Co-funded with University of Edinburgh

Humans cannot replace motor neurons that are lost in ALS. However, we have found that zebrafish, an important animal model, readily replace motor neurons from adult stem cells that are already resident in the damaged spinal cord. By identifying the molecules involved and showing how the mechanism of motor neuron regeneration in zebrafish can be controlled, our studies will inform future therapies aimed at rescuing or replacing diseased motor neurons in ALS.

Hongjun Song, PhD
Johns Hopkins School of Medicine
Model ALS Using Human Pluripotent Stem Cells
Funding for this project was made possible by the Muscular Dystrophy Association

Much has been made about using neural stem cells – those in the adult central nervous system of humans and other mammals – as possible repair agents once ALS is slowed or cured. But not many people realize adult neural stem cells also provide a powerful way to study cell behavior. And with Packard scientists recently showing that interactions between motor neurons and their surrounding cells are crucial to the course of the disease, the time is ripe for a good way to study them.

New Packard researcher, Hongjun Song, is preparing laboratory cultures of stem cells to model normal cell interactions and contrast them with what occurs in ALS. He chooses these specific stem cells because they're endowed with nervous system characteristics but, unlike adult nerve cells taken from the body, they reproduce and survive in lab dishes. Also, as stem cells, they can morph into the various types of cells in the nervous system.
Song will work with both normal stem cells and those carrying the mutant SOD1 genes that can trigger ALS characteristics. He'll also use both mice and human cells in his cultures. His system should let him follow the course of disease at a cell level. It should also show how crucial each type of nervous system cell is to the process.

Thomas Brushart, MD
Johns Hopkins School of Medicine
The Role of Pathway-Derived Growth Factors in Motor Axon Regeneration

Regenerating motor neurons can distinguish between nerve pathways that lead to skin and those that lead to muscle. We have recently shown that these pathways differ in the types or patterns of release of the growth factors that they produce. However, we don't yet understand how that plays a part in motor neuron growth toward muscle targets.

My work for the Packard Center aims to shed light on the process, largely by creating a small, controlled system to study. Our cultures will consist of sections of spinal cord containing motor neurons placed close enough to living nerve to enable the motor neurons to regenerate into the nerve.
In this situation, we can explore the role of different growth factors and even cell structure that affects motor neuron outgrowth. We hope to apply this knowledge to patients, ultimately, to develop ways to overcome the effects of injury or disease in the nervous system.

Albert Ludolph, MD & Philip Wong, PhD

University of Ulm / Johns Hopkins School of Medicine
Development of transgenic mice carrying dynactin mutations associated with sporadic ALS
Partial funding for this project was made possible by the Muscular Dystrophy Association

Mutations in the protein dynactin, part of a neuron's internal transport system, are suspect as a cause of amyotrophic lateral sclerosis. However, since the genetic findings in more than 2,000 patients and controls cannot reveal a cause-effect relationship for each of the mutations, we propose to investigate the detected sequence changes in transgenic mice.

Ahmet Hoke, MD, PhD
Johns Hopkins School of Medicine
Pleiotrophin in Motor Neuron Disease
Partial funding for this project was made possible by the Muscular Dystrophy Association

In ALS, current attempts at treating the illness are directed at promoting the growth of motor neurons without addressing the issue of changes that occur in the distal portions of the peripheral nerves. Local factors within the distal portions of the nerve may play an important role in degree of success during regeneration of motor neurons into the target tissue. Glial cell-line Derived Neurotrophic Factor (GDNF) is very important in motor neuron regeneration and survival. This project has two goals: (1) To transplant C17.2 stem cells in a model of regeneration after prolonged denervation in order to improve degree of motor regeneration; (2) To develop robust and reliable measures of motor regeneration that we can measure at the target tissue using electrophysiological and histological methods.

Jean-Pierre Julien, PhD
Laval University, Quebec
Development of Passive Immunization Approaches for ALS Caused by SOD1 Mutations

Our previous studies demonstrated therapeutic effects of vaccination against mutant SOD1 in mice models of ALS. In the past year, we tested a passive immunization based on intracerebroventricular (ICV) infusion in G93A-SOD1 mice of monoclonal antibodies specific to misfolded forms of SOD1. One antibody succeeded in prolonging the lifespan on G93A-SOD1 mice in proportion to the duration of treatment. Interestingly, the variable Fab fragment of this anti-SOD1 antibody was sufficient to confer protection in G93A-SOD1 mice. The dispensability of Fc region open new avenues for the use of single-chain variable fragments (scFv) or intrabodies of smaller size and with less immunogenicity. Here, we propose to use three different strategies for the testing of anti-SOD1 scFv antibodies for treatment of ALS caused by SOD1 mutations. First, we will test the therapeutic effects of anti-SOD1 scFv antibodies when infused ICV in G93A-SOD1 mice. Second, we will test a gene therapy approach based on adeno-associated virus (AAV) encoding scFv antibodies. Third, we will generate transgenic mice bearing Thy1-scFv constructs to test the therapeutic efficacy of scFv antibodies with or without signal peptide (intrabodies) for cellular secretion.

Thomas Lloyd, MD, PhD & Alex Kolodkin, PhD
Johns Hopkins School of Medicine
A Drosophila Model of Motor Neuron Disease Using Mutations in p150 Dynactin
Partial funding for this project was made possible by the Muscular Dystrophy Association

The fruit fly, Drosophila melanogaster, provides one of the most powerful gene-based systems for studying development and biology of the neuromuscular system. Because of the ability to express mutant human genes in Drosophila, the flies have recently been used as models of many neurodegenerative illnesses such as Alzheimer's, Parkinson's and Huntington's diseases. Such models allow rapid screening of all other genes, to search for those that modify the disease process in some way. They also reveal potential drug targets.

We're exploring mutations in genes involved in internal transport of materials within a motor neuron's axons, specifically those associated with motor neuron degeneration in humans. Since these genes are highly conserved from flies to humans, we expect that similar mutations in the fly will reproduce characteristics of the human disease. Our goal is to create a genetic model of motor neuron disease in Drosophila and then use this model to search for new drug targets for ALS.

John Gerdes, PhD & Richard Bridges, PhD(Renewal)
University of Montana
Cerebral Positron Emission Tomography (PET) Imaging Agents for Monitoring ALS Therapy
Dr. Gerdes is the Packard Center's Boye Foundation Researcher for 2006 and 2008

The EAAT2 molecule is a cell membrane protein that removes excesses of the neurotransmitter glutamate. Abnormalities in EAAT2 quantity or in its behavior have long been tied to ALS. That could make the molecule a good indicator, or biomarker, of nervous system health. At some point, it could provide a way to measure if treatment is effective.
In our supported research, we hope to create a radioligand (tracer) molecule targeted to the EAAT2 protein. The tracer will enable us to detect the EAAT2 biomarker noninvasively within the brain and spinal cord, using positron emission tomography (PET) imaging. Our challenge comes in designing a tracer with a unique chemical structure ? a molecule with a high affinity for the EAAT2 target protein, one that can penetrate the brain?s natural barriers and that reaches specific central nervous system tissues. Ultimately, data from our studies may lead to a noninvasive way to monitor ALS in the clinic.

Weichun Lin, PhD (Renewal)
UT Southwestern
Neuromuscular Synaptic Degeneration in Motoneuron Diseases

Weichun Lin’s team has created a novel transgenic mouse—based, in part, on a fairly newly-discovered, inheritable ALS mutation—that develops motor neuron disease with key features of the human disease. The mice become paralyzed at 5 months of age, and the paralysis progresses to the rest of the body within ten months. The specific cell error the model mice show should shed light on poorly-explored aspects of the ALS process, namely, events at the motor neuron synapse and those involving the cell’s system for removing damaged proteins. Lin’s grant supports his month by month study of motor neurons and synapses in this new model. He hopes to see how synaptic and conduction changes relate to outward signs of the disease.

Maiken Nedergaard, MD, PhD (Renewal)
University of Rochester
Identification of early changes in astrocytic gene expression in a mouse model of ALS using FACS-Array analysis

Astrocytes are the most abundant central nervous system cell, yet their having a role in the progression of ALS has been discovered only recently. The star-shaped cells configure themselves into a close network, creating micro-environments where they contact neurons. These areas are critical for proper activity of neurons at synapses.
We plan to analyze the physical changes that astrocytes undergo throughout the progression of ALS, to determine how changes in this highly structured network, or syncytium, as it's called, influence motor neurons' susceptibility to cell death.
We also plan to study astrocytic genes that are misregulated in very early phases of the disease - before symptoms - in an attempt to identify early markers and the earliest-disrupted chemical pathways. This, we believe, could shed light on ways that astrocytes affect motor neuron cell death.

John W. Griffin, MD & Mohamed Farah, PhD
Johns Hopkins School of Medicine
New Tools for Assessment of the Pathology of Experimental Motor Neuron Diseases
Funding for this project was made possible by the Muscular Dystrophy Association

We have developed new techniques to investigate pathology of the peripheral nervous system with greater accuracy and efficiency. Now we're using them successfully to study growth factor and other types of cell signaling, nerve regeneration, and the effects of nerve demyelination. Applying these approaches to ALS models is especially timely; we simply don't know the extent and pace of neuronal changes in these disorders. A secondary but important goal is to find a simple, rapid indicator of the state of health of the peripheral nervous system, one that can be used by any investigator to any rodent model of motor neuron or peripheral nerve disease.

Ron Oppenheim, PhD & Carol Milligan, PhD
Wake Forest University
Early Changes in ALS: Motoneuron Cell Body and Synaptic Stripping

In ALS, the presumed cause of muscle movement loss has always been the death of motor neurons. New research is showing, however, that while motor neuron death does occur, it's the pulling away of neuron from muscle that appears to precipitate disease symptoms. Our work will study early changes in biology that occur at the motor neuron/muscle junction and relate them to earlier or subsequent changes in the motor neuron proper. We use a multidisciplinary approach to discover which portion of the nervous system shows ALS's earliest changes. Our intent is to find a biomarker for the disease - one that will report on the usefulness of new therapies.

Philip C. Wong, PhD
Johns Hopkins School of Medicine
Generation and Characterization of Wildtype and ALS-linked TDP-43 Mice (Renewal)

How disease arises in sporadic ALS remains elusive. The recent discovery of mutations in a gene called TDP-43 (TAR DNA-binding protein), linked to both sporadic and familial ALS, provides the opportunity to elucidate the underlying cause of sporadic ALS. In this project, we investigate whether an ALS-associated mutant TDP-43 protein can cause motor neuron disease in mice. If so, a mouse model will be available to clarify how disease arises in sporadic ALS and for design of therapeutic strategies to attenuate this devastating disease.

Giovanni Manfredi, MD, PhD
Weill Medical College, Cornell
Mitochondrial Axonal Transport Defects in ALS Motorneurons
Partial funding for this project was made possible by the New York Community Trust

Giovanni Manfredi and others studying motor neurons in mouse models of ALS have noticed that the animals' mitochondria – the minute organs that produce most of a cell's energy – are damaged. The same is true in ALS patients, who also appear to have abnormal mitochondria.

Using mice carrying a mutated form of the cell enzyme SOD1 that's responsible for some types of inherited ALS, Manfredi has begun clarifying the damage process. His hypothesis is that their mitochondrial injury results in a loss of energy that trips motor neuron decline. Additionally, mitochondrial damage in SOD1 mouse models also appears to trigger apoptosis, cells' hard-wired program for death.

For now, Manfredi's focus rests on the activities of SOD1. The enzyme, he's discovered, can reside in mitochondria as well as in cell cytoplasm. But he says only mitochondria containing mutant SOD1 display features typical of injury.

Since joining the Center, Manfredi's begun looking at various different SOD1 mutations, to determine whether mitochondrial damage is a common denominator in all of them. By understanding SOD1's role in affecting mitochondrial health, he hopes to explain the overall effect on motor neurons in cell and animal models created in his laboratory.

J. Paul Taylor, MD, PhD
St. Jude Children's Research Hospital
A Drosophila model to investigate the role of TDP-43 in ALS

Motor neurons of ALS patients typically contain abnormal deposits of the protein TDP-43. Some researchers have suggested such deposits are important in tripping ALS or in its progress. There is, however, no concrete proof of this. We have developed a model of ALS in the fruit fly, Drosophila by introducing the human TDP-43 gene. We hope to use this model to understand the protein's role in the disease.

Wim Robberecht, MD, PhD
University of Leuven, Belgium
Validation of the use of a zebrafish model as a screening tool to identify modifying genes in Amyotrophic Lateral Sclerosis

Using a zebrafish model to study the mechanism of ALS, we have identified a gene called ephA4 which rescues the motor abnormalities induced by mutant SOD1. We now intend to investigate the role of this gene in ALS and want to study whether genetic alterations in this gene are associated with ALS in humans. Furthermore, we want to explore the therapeutic potential of interfering with this receptor.

Abraham Acevedo-Arozena, PhD
Medical Research Council, Oxford UK
Characterization of a unique mouse model of ALS

We are characterizing a new, unique mouse model of amyotrophic lateral sclerosis (ALS). This new model carries a point mutation in the mouse SOD1 gene that is identical to human cases of familial ALS. This is the first mouse model carrying this specific mutation in SOD1 that develops motor neuron degeneration and we will be undertaking in depth phenotypic characterization of these new mice to understand the human condition. The mice are a new and important model because they are likely to mimic the biochemistry of the human condition better than existing transgenic mice.

Richard Bedlack, MD, PhD
Duke University

Patients with ALS sometimes consider alternative or off-label treatments for their disease. It is difficult, however, to get accurate information on their costs, side effects and potential benefits. We will use email, Twitter and other social media to bring patients, clinicians and scientists together to document the facts about various alternative and off-label therapies being offered for ALS.

Steven J. Burden, PhD
New York University
Prolonging longevity and maintaining neuromuscular synapses in SOD1 G93A mice by increasing MuSK expression/activity

Our prior experiments demonstrate that a modest increase in MuSK expression is sufficient to maintain compromised neuromuscular synapses and raise the possibility that increasing MuSK expression/activity in other circumstances, including ALS, may prevent or delay motor axon withdrawal and extend longevity. We propose to determine whether increasing MuSK expression is sufficient to prolong longevity and delay motor axon withdrawal in SOD1 G93A transgenic mice.

Jonathan Glass, MD
Emory University
Novel Therapeutic Interventions in the fALS Mouse

Our earlier Packard work showed that the degeneration of a motor neuron's leading end, the most distant part of the extending axon, is one of the earliest changes in the SOD1 mouse that models ALS. This is likely the same in human disease.

The work has prompted studies by other Packard investigators, and those outside of Packard, to focus on this area as a possible seedbed of ALS . We, ourselves, have advanced this field by studying how the mutant SOD1 gene – a source of human familial ALS – carries out this distal motor neuron damage. We've examined the phenomenon of having an excess of free radicals – oxidative stress – in motor axon degeneration, and have been studying the importance of normal SOD1 within the mitochondria, the cell's powerhouses, in keeping distal motor axons healthy.

While we are continuing our study of axonal oxidative stress, this latest grant work aims to clarify why motor neurons, specifically, are so vulnerable in this mouse model of human familial ALS.

Alfred Goldberg, PhD
Harvard University
Mechanisms for stimulating autophagy and proteasomal degradation to clear misfolded proteins

ALS, like several other major neurodegenerative diseases, results from a buildup in the affected neurons of misfolded proteins, whose accumulation is toxic. Our studies build upon recent insights about the mechanisms cells naturally use selectively to destroy such misfolded proteins. We aim to investigate molecular pathways we could manipulate to enhance the neuron’s ability to degrade such dangerous molecules and, thus, to prevent disease progression.

Noah Lechtzin, MD & Ben P. Yuhas, PhD
Johns Hopkins School of Medicine / Yuhas Consulting Group, LLC
Identifying Interactions Between Prescribed Drugs and Survival Rates of ALS Patients Using Medicare Data

Our objective is to demonstrate the usefulness of studying Medicare claims data to provide insight in making prognoses for ALS patients. We’ve proposed a pilot study to look at the relationship between prescribed drugs and survival rates in ALS and to determine if that warrants a more comprehensive investigation.

Nicholas Maragakis, MD
Johns Hopkins School of Medicine
A non-neuronal, human cell-based transplantation paradigm targeting respiratory dysfunction in ALS
Funding for this project was made possible by the Muscular Dystrophy Association

Most ALS patients die from respiratory failure as the muscles that control breathing become weak. While many cell transplantation strategies have focused on replacing the motor neurons that service those muscles, our work focuses on use of human glial stem cells to protect the motor neurons in the first place. We're exploring this first by transplanting glial stem cells into a rat model of ALS. The cells are targeted to the neck region of the spinal cord - the area containing motor nerves that innervate breathing muscles. Measurement of various signs will show if disease course has slowed. Our hope is that that targeting these specific regions will ultimately lead to human glial stem cell trials aimed at significantly prolonging patients' lives.

Richard Morimoto, PhD
Northwestern University
The Proteostasis of ALS

The focus of my current project is to understand how organisms sense and respond to physiologic and environmental stress through the activation of genetic pathways that integrate stress responses with a variety of molecular and cellular responses. We believe that the expression of ALS-associated proteins (SOD1, TDP-43 and FUS) interferes with protein homeostasis (proteostasis) leading to the failure of dynamic cellular processes. To address this, we propose to establish new genetic models for expression of these proteins for direct comparison of the biochemical, biophysical, cellular, and physiological properties during C. elegans development and aging. These experiments will establish whether aggregates of ALS-associated mutant proteins shut down essential cellular functions

Philip C. Wong, PhD
Johns Hopkins School of Medicine
Physiological Role of TDP-43: development of conditional TARDBP knockout mice

How ALS arises in sporadic ALS patients remains elusive. We believe the recent discovery of mutations in the TDP-43 gene – one linked both to sporadic and familial ALS – will help lead us to understand the cause.

To do that, it’s first necessary to determine what part the gene’s product, a protein also called TDP-43, plays in motor neurons. We intend to do this indirectly, by studying adult mouse models that lack the TDP-43 protein. A relatively new technique lets us turn off the TDP-43 gene at will. So far, preliminary data suggests that in motor neurons, the TDP-43 protein, in turn, regulates a protein called SMN. (It’s of interest to know that loss of SMN causes Spinal Muscular Atrophy, a motor neuron disease that afflicts infants.

Yimin Zou, PhD
University of California San Diego
Regeneration and Degeneration of Cortical Neurons

We study the basic mechanisms of how motor neurons are connected with muscle targets during normal development. Understanding the mechanism of motor axon outgrowth and guidance will potentially shed light of the cause of motor neuron degeneration. In the future, when stem cell techniques become available to help regenerate the impaired motor neurons, methods will need to be developed to guide these motor neuron axons to find their proper targets. Our studies will potentially provide such molecular tools to guide regenerating motor axons to reconnect to muscle targets to cure ALS patients.

Steven Finkbeiner

Our Experts

Gladstone Institutes, UCSF
Two recently discovered genes that have been associated with both familial and sporadic forms of ALS encode the related proteins TDP43 and FUS cause neuron death in ALS.
Meet Our Experts