October 08, 2009 

The ALS Association Announces The Milton Safenowitz
Post-Doctoral Fellowship for ALS Research Grants

Three young investigators funded by the Milton Safenowitz Post-Doctoral Fellowship are engaged in innovative projects to accelerate progress in the field. The ALS Association is especially committed to bringing new concepts and methods in ALS research and young scientists play an important role in this process. Funding is through the generosity of the Safenowitz family and the Greater New York Chapter of The ALS Association in memory of Milton Safenowitz who died in 1998 of the disease.

TDP-43 as a Biomarker for ALS.
Tania Gendron, Ph.D. Mayo Clinic College of Medicine, Jacksonville, Florida

TAR DNA-binding protein 43 (TDP-43) is the major component of neuronal and glial inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLDU). In inclusion-bearing neurons, TDP-43 is abnormally phosphorylated and truncated, producing fragments of 25 and 35 kDa. Missense mutations in the TDP-43 gene are observed in sporadic and familial forms of ALS, supporting a direct link between TDP-43 abnormalities and ALS. Thus, TDP-43 may be a potential biomarker for ALS. Indeed, TDP-43 can be detected in plasma and CSF and TDP-43 levels are elevated in cases of ALS, FTLD and Alzheimer’s disease. In one study, ALS patients had significantly higher levels of CSF TDP-43 compared to age-matched controls. These studies provide preliminary evidence that TDP-43 could be useful for the diagnosis of ALS. Nonetheless, the development of assays specific for pathological TDP-43, such as phosphorylated or truncated forms, will likely improve their sensitivity.

"I am excited and grateful to be awarded a Milton Safenowitz Post Doctoral Fellowship. This award will be instrumental in developing assays for the detection of TDP-43 (a protein implicated in the disease process of ALS) in biological fluids. These assays will be useful to study the role of TDP-43 in ALS and, importantly, will have clinical applications that may eventually benefit ALS patients. The assays may provide a molecular means for the early diagnosis of ALS and for monitoring disease progression. As such, these assays may prove valuable for assessing response to experimental therapies in ALS therapeutic trials."

Defining the role of ER stress and the Unfolded Protein Response (UPR) in the pathogenesis of ALS
Soledad Matus, Ph.D. Institute of Biomedical Sciences, University of Chile, Santiago:

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive and deadly adult-onset motor neuron disease characterized by muscle weakness, atrophy, paralysis and premature death. The majority of ALS patients lack a defined hereditary genetic component and are considered sporadic, while approximately 10% of cases are familial. The primary mechanism responsible for the progressive motor neuron loss in ALS remains unknown. Clues have been obtained from families who have a genetic form of ALS that is accompanied by a mutation in an important protein called superoxide dismutase (SOD1). It has been suggested that perturbation in the function of a subcellular organelle called the endoplasmic reticulum (ER) may determine the aggregation and neurotoxicity of ALS-linked mutant SOD1. The investigators have obtained preliminary data supporting an involvement of this stress response in the pathogenesis of disease-related mutant SOD1 protein. In this project the Dr. Matus aims to perform a systematic analysis to define in detail the contribution of each essential component of this pathway to motor neuron dysfunction in ALS using experimental ALS models and the analysis of samples from ALS patients. This research may lead to the discovery of new targets to design novel therapeutic strategies to treat this fatal neuromuscular disease.

“During my PhD studies I developed a biomedical project in the field of neurobiology and aimed to understand the connection between autoimmunity and neurological disorders in the context of human pathology. I realized that I have a strong motivation to undergo disease-oriented research with biomedical applications. I am currently working at the University of Chile, particularly focused in studying the role of protein misfolding and organelle stress in cellular and animal models of ALS. In the future I would like to establish a career in biomedical research oriented to ALS pathogenesis, a subject poorly addressed in my country, and this fellowship definitively is crucial to pursue this aim”.

Determining RNA metabolism alterations in ALS using high-throughput sequencing technology
Clotilde Lagier-Tourenne, M.D., Ph.D. The Ludwig Institute for Cancer Research, UCSD, CA

Recent identification of ALS-causing mutations in two genes encoding for TDP-43 and FUS/TLS, respectively, has initiated a paradigm shift in understanding ALS pathogenesis. TDP-43 and FUS/TLS have striking structural and functional similarities, suggesting alterations in RNA processing as key in ALS. It is now fundamental to decipher the precise roles of TDP-43 and FUS/TLS in RNA metabolism regulation and how alterations in them may underlie ALS pathogenesis. Dr. Lagier-Tourenne proposes to use state of the art methods in sequencing to obtain an unbiased map of their RNA targets and potentially identify candidate genes whose altered splicing is central to neurodegeneration. Importantly, TDP-43, which is mutated in a restricted number of ALS patients, is also abnormally aggregated in most of ALS sporadic cases and in other neurodegenerative disorders. It is our hope that understanding of TDP-43 and FUS/TLS normal functions and pathogenic properties will serve as the foundation for development of potential therapeutic approaches for the vast majority of ALS patients.

"I started my postdoctoral training at a very exciting period for ALS research when the identification of TDP-43 and FUS/TLS mutations in ALS patients pointed out the importance of RNA metabolism regulation in ALS pathogenesis. Importantly, the Milton-Safenowitz postdoctoral fellowship from The ALS Association will allow me to expand my research focus and broaden my research skills, including expertise in high throughput genomics to uncover neurodegenerative disease mechanisms."

CALL FOR ABSTRACTS

Please email researchgrants@alsa-national.org  to learn more about the post-doctoral fellowship program. Abstracts for 2010 funding are due 8 January, 2010.