The ALS Association
ALS Ice Bucket Challenge Progress

2017 Milton Safenowitz Fellowship Program for ALS Research Recipients

The Association is proud to support the development of bright, young scientists through the Milton Safenowitz Postdoctoral Fellowship. The Safenowitz family, through The Greater New York Chapter of The ALS Association, founded the award in memory of Mr. Safenowitz, who died of ALS in 1998. These awards are to encourage and facilitate promising young scientists to enter the ALS field. Fellows work with a senior mentor and receive extensive exposure to the ALS research community through meetings and presentations. After completing this fellowship, approximately 90 percent of the awardees stay in ALS research. They go on to establish their own laboratories to continue studying ALS and mentor more ALS researchers along the way.

Anthony Giampetruzzi, Ph.D., University of Massachusetts Medical School, Worcester, Mass.
*Funding also made possible by the Massachusetts Chapter of The ALS Association
Title: Identifying therapeutics for ALS using ALS-linked mutant Profilin-1

Summary: The neurodegenerative disease amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure. There is strong evidence that disruption to the cytoskeleton and its functions in motor neurons play a significant role in the disease. The cytoskeleton has many important functions, including providing shape and organization to the cell. Mutations in the PFN1 gene, which encodes for the actin binding protein profilin 1, have been linked to ALS and cause changes to the cytoskeleton that mimic changes commonly found in ALS. We have found that the presence of ALS-linked profilin 1 in neurons leads to decreased survival of neurons in culture. In this proposal, we will identify potential therapeutic targets for the treatment of sporadic and familial ALS by performing a screen to identify factors that increase the survival of ALS-linked mutant profilin 1 possessing neurons. The factors identified that increase survival are potential therapies for familial and sporadic ALS that can be immediately tested in animal models of the disease. In addition, the factors identified will also provide novel insight into pathways involved in neuronal death in ALS. These findings will therefore be very impactful in designing future treatments for ALS.

Maria Purice, Ph.D., St. Jude Children’s Research Hospital, Memphis, Tenn.
Title: Linking TDP-43 pathology with stress granule dynamics

Summary: Stress granules (SGs) are membrane-less organelles that form in the cytoplasm of cells in response to environmental stressors. Similar to how oil droplets act when mixed with water, SGs assemble by liquid-liquid phase separation, which is mediated by low complexity sequence domains (LCDs) that are present in RNA-binding proteins such as TDP-43, hnRNPA1 and FUS. Prior work in the Taylor lab has established that mutations in LCDs that are causative of ALS also disturb dynamic assembly and disassembly of SGs. An important missing link is the relationship between altered SG dynamics and the hallmark pathology of ALS; namely, fibrillar deposits of pathogenic TDP-43. Because SGs are active liquids, we hypothesize that when the material properties of SGs (i.e., assembly/disassembly rates, mobility, and viscosity) are impaired, the residence time of TDP-43 in this high concentrated environment increases, making it more prone to aggregate and become pathogenic. Our findings will provide the foundation for understanding the relationship between the mechanisms that regulate SG dynamics and their potential conversion into TDP-43-positive protein aggregates that are the hallmark pathology of ALS.

Yue Li, Ph.D., The Scripps Research Institute, Jupiter, Fla.
Title: Development of RNA-templated small molecules to treat C9ALS/FTD

Summary: ALS is the most common motor neuron disease leading to chronic muscle weakness and spasticity due to progressive neurodegeneration. On the cellular level, ALS can be caused by a genetic mutation that produces toxic RNAs. The ALS RNAs are toxic for various reasons including production of toxic proteins, resulting in neuronal cell death. In a recent study, we designed a drug that binds the ALS RNA and reduces disease related symptoms in ALS patient-derived cells. Here, we propose to optimize our compound into precision medicines that target the ALS-causing RNA repeats and to develop diagnostic tools. In our precision medicine approach, an ALS-affected cell synthesizes its own drug; that is, the drug is only made at the needed site. Since the drug is only synthesized in ALS-affected cells and not in healthy cells, there is less likelihood for side effects. Finally, we propose to develop diagnostics tools to image these pathogenic RNAs in ALS patient cells.

Nibha Mishra, Ph.D., Massachusetts General Hospital, Boston, Mass.
Title: Identifying determinants of FUS nucleocytoplasmic localization by CRISPR/Cas9 genetic screen in ALS patient cells

Summary: Mutations and/or cytoplasmic mislocalization of FUS are associated with severe form of juvenile ALS but the factors influencing aberrant nucleocytoplasmic transport of FUS are not well understood. Previously our group FUS has demonstrated role of FUS in RNA processing and splicing in patient derived cells. In this proposal I will seek to identify genes associated with aberrant nucleocytoplasmic transport of FUS using genome wide CRISPR based screening in isogenic neurons with FUS mutation. Recently we have developed a flow cytometric based assay that separates fibroblasts expressing cytoplasmic mutant FUS from cells with nuclear FUS protein. Also, my colleagues have engineered an isogenic neuronal cell line with FUS mutation. So firstly, I will first optimize this assay for isogenic human neurons with FUS P525L mutation (Aim 1). Then in collaboration with Broad Institute will perform a pooled genome-wide CRISPR/Cas9 screen (Aim 2) to identify genes associated with aberrant neucleocytoplasmic transport of FUS. Finally, I will optimize the functioning of these genes in patient derived neurons (Aim 3). I believe that this innovative approach has the potential to uncover crucial pathways that may be therapeutically targeted in ALS.

Meredith Corley, Ph.D., University of California San Diego, San Diego, Calif.
Title: Accurate RNA structural studies of transcripts targeted by RNA binding protein hnRNP A2/B1

Summary: RNA binding proteins (RBPs) are a diverse family of proteins that interact with and manage cellular RNA molecules. ALS diseases are frequently accompanied by abnormalities in RNA binding protein function. Thus, studying the RNA binding partners and function of specific RBPs in normal and disease states has become essential to ALS research. An inherent aspect of RBP function is interaction with RNA binding sites, which is partially governed by intrinsic features of the RNA partner. The RBP binding sites in RNAs are characterized by both primary structure (i.e. nucleotide sequence) and secondary structure (spatial interactions between RNA nucleotides). The primary sequence motifs that recruit specific RBPs are commonly identified in RBP studies and are much easier to determine than any secondary structure specificities. Thus, the secondary structures that populate RBP binding sites are often underappreciated and understudied, even though they are an important aspect of RBP binding and function. In our work we will use state of the art RNA structure probing methods to characterize the secondary structures in RNA binding sites occupied by an ALS-related RBP, hnRNP A2/B1. Additionally, we will study the changes to RNA binding sites that result from an hnRNP A2/B1 mutant known to cause ALS.

Sarah Ackerman, Ph.D., University of Oregon, Eugene, Ore.
Title: Contribution of astrocyte function and dysfunction to ALS

Summary: Recent studies have shown that astrocytes, a support cell within the nervous system, contribute to motor neuron loss and dysfunction in ALS. Astrocytes are the most abundant CNS glial cell, and they serve a variety of biological functions essential for neuronal health and longevity, including provision of nutrients and regulating connections between neurons. I will take advantage of newly developed genetic tools in the fly model system to determine how astrocytes specifically support motor neuron function and survival, and how these properties are impaired in animal models of ALS.

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