2013 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.
Russell McLaughlin, Ph.D., Trinity College Dublin, Dublin, Republic of Ireland
*Funded by The ALS Association, Greater Chicago Chapter, through the state of Illinois
Title: Molecular rapprochement of neurology and psychiatry: are ALS and schizophrenia biologically convergent?
Summary: In work previously supported by his Milton Safenowitz Postdoctoral Fellowship, Dr. McLaughlin found that ALS families have incidences of schizophrenia and suicide. Also, both ALS and schizophrenia are partially polygenic, meaning that more than one genetic variation in a person can cause disease. The goal of his is study is to understand whether ALS and schizophrenia are genetically correlated and whether we can exploit our current body of schizophrenia knowledge to better understand ALS disease. Dr. McLaughlin found that they are genetically correlated and leveraged this correlation to identify novel ALS genes. Studies are ongoing to validate identified genes and to test how they impact ALS disease mechanism.
Qiang Zhu, Ph.D., Ludwig Institute at University of California, San Diego, La Jolla, Calif.
Title: Gain of toxicity from C9orf72 ALS/FTD mutation is therapeutically alleviated with antisense oligonucleotides
Summary: Dr. Zhu and colleagues developed a mouse model that over-expresses the C9orf72 expansion mutation. They found that these mice develop typical pathological signatures and demonstrate learning and memory deficits and anxiety. As a potential therapy, they used antisense oligonucleotide therapy (ASOs) to selectively decrease the expression of mutant C9orf72, not the normal C9orf72 with a single dose. The ASO treatment successfully rescued the characteristics stated above. An ASO clinical trial targeting C9orf72 mutations is slated to start in the first quarter of 2017 for patients living with ALS.
Marka Van Blitterswijk, M.D., Mayo Clinic Florida, Jacksonville, Fla.
*Funded by The ALS Association, Greater Chicago Chapter, through the state of Illinois
Title: Predicting the phenotype in C9orf72 expansion carriers using machine learning
Summary: Dr. Van Blitterswijk and team set out to identify factors that may drive the substantial variability in people carrying a repeat expansion in C9orf72, the most common familial cause of ALS. These factors could also serve as ALS biomarkers [a molecular signature in the brain or cerebral spinal fluid or structural change in the brain]. She found changes in transcript variant 1 of C9orf72, methylation levels and a secreted protein that could potentially be used to as an ALS biomarker to improve ALS diagnosis, to predict disease progression, or to monitor the effects of a potential therapy.
Jonathan Labbadia, Ph.D., Northwestern University, Chicago
*Funded by The ALS Association, Greater Chicago Chapter, through the state of Illinois
Title: Programmed re-modeling of heat shock response underlies onset of ALS
Summary: The causal relationship between aging and disease remains mysterious; however, an age-related change in the ability to prevent protein damage has been put forward as a trigger for the onset of neurodegeneration. If DNA is the "blueprint of life," then the proteins it encodes are its effectors. Cells contain a huge number of proteins that are integral to cell function. If proteins become misfolded or mislocalized they can cause disease; therefore, maintaining protein integrity is essential for health. To achieve this, cells have evolved the protein homeostasis network (PN), a combination of pathways that suppress the presentation and persistence of aberrant proteins. As cells age, the PN becomes compromised, a phenomenon that is exacerbated in many age-related diseases, including ALS. Incredibly, aging studies in worms have revealed that a "switch-like" re-modeling of the PN is an early event in adulthood. Therefore, Dr. Labbadia and colleagues hypothesize that genetic "re-programming" of the PN underlies the increased susceptibility of individuals to protein misfolding and onset of ALS with age. They will test this hypothesis by identifying the molecular and genetic basis of PN re-modeling and use this knowledge to determine the impact of genetically re-engineering the PN on disease presentation in models of ALS.
Yang Li, Ph.D., Barrow Neurological Institute, Phoenix
Title: Structure and function of a new candidate ALS biomarker RBM45 (RNA binding protein 45)
Summary: Members of this lab have recently identified a novel RNA-binding protein RBM45 implicated in ALS and FTLD. RBM45 was initially identified through its altered levels in the cerebrospinal fluid of ALS patients. Further characterization indicates that RBM45 localizes to cytoplasmic inclusions and co-localizes with TDP-43 and ubiquitin inclusions in ALS and FTLD patients. Since joining the lab, Dr. Li has been focusing on how RBM45 is involved in the molecular pathway of neurodegeneration. She has discovered the physical interactions between RBM45 and other ALS-associated proteins and found that RBM45 can self-interact. She will continue to characterize the protein-protein interactions and the self-aggregation propensity of RBM45 in this study. She will also identify the RNA species that are bound by RBM45 by using a novel non-radioactive CLIPseq approach termed TAP-CLIP. TAP-CLIP can be applied to any RNA-binding protein to identify their RNA targets. This proposed study will provide novel insights into the function of RBM45 and its potential contribution to ALS pathogenesis.
Jennifer Gass, Ph.D., Mayo Clinic, Jacksonville, Fla.
*Funded by Jay & Toshiko Tompkins
Title: Understanding the relationship between progranulin, sortilin1 and TDP43
Summary: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord, which result in muscle weakness, atrophy and spasticity. A major pathological feature of ALS is the abnormal accumulation of a protein called TDP43. In disease, TDP43 is redistributed from the nucleus to the cytoplasm of a cell, truncated and abnormally phosphorylated. Mutations in the progranulin gene (GRN) resulting in decreased production of the progranulin protein are associated with TDP43 pathology in frontotemporal lobar degeneration, a neurodegenerative disease sharing many clinical and pathological features with ALS. Recently, GRN mutations were also discovered in patients with ALS. Within the brain, progranulin levels are regulated by its neuronal receptor, sortilin (SORT1). Currently there is no cure for ALS; however, therapeutic treatments that inhibit the aberrant aggregation, mislocalization and truncation of TDP43 may prove beneficial for the treatment of ALS. The goal of this project is to determine whether dysfunction with SORT1/progranulin exacerbates TDP43 pathology and, ultimately, if pharmacological progranulin enhancement alleviates TDP43 pathology associated with ALS. These studies will provide further insight into the mechanisms causing pathological TDP43 accumulation and provide a therapeutic strategy for the treatment of ALS.
Zhaoming Su, Ph.D., The Scripps Research Institute, La Jolla, Calif.
Title: Rational design of small molecules targeting GGGGCC expanded repeat in C9ORF72 gene implicated in ALS-FTD
Summary: Amyotrophic Lateral Sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative diseases with a common genetic cause: an expanded repeat of the sequence GGGGCC in the C9ORF72 gene. Like all genes, C9ORF72 is transcribed into RNA, which encodes proteins that complete most of the work in a cell. Once transcribed into RNA, the repeat causes ALS-associated defects. The researchers have previously developed a strategy to design drugs that target other expanded RNA repeats that cause disease. These designed drugs alleviated disease-associated defects in cellular and animal models. They will use similar design principles and strategies to develop drugs that bind the RNA expansion and improve ALS-associated defects. They have identified two lead drug candidates that bind the expansion in vivo and improve an ALS-associated defect. Based on these promising results, they propose to: (i) optimize the two compounds by synthesizing and screening millions of derivatives for binding the expansion; (ii) study the optimal compounds for alleviating two ALS-associated defects in patient- derived cell lines. The best compounds serve as potential therapeutics for ALS; (iii) identify all biomolecules that the drugs bind in ALS patient-derived cells, thus determining drug mode of action and selectivity.
