This application addresses broad Challenge Area (15): Translational Science and specific Challenge Topic, 15-NS-104: Early-stage Therapy Development. Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) is a devastating neurodegenerative condition that kills nerve cells in the brain and spinal cord that control the muscles, leading to progressive weakness and death within 3-5 years. Currently, no treatment can slow the progression of the disease, thus raising the urgency for developing new animal models of ALS that can be used to identify novel therapeutic strategies. Recently mutations in a new gene, FUS/TLS, have been identified to cause ~5% of familial ALS cases. The mechanism(s) by which these mutations cause the disease is not clear, but they may overlap with defects in other known ALS genes such as TDP-43, senataxin, and dynactin. These genes may function in the processing, delivery, or regulation of RNA molecules, and thus, defects in these functions may underlie motor neuron vulnerability in ALS. The direct causal link of mutant FUS/TLS to ALS provides an opportunity to develop novel in vivo ALS models that will accelerate the identification of new treatment target(s) for ALS. To generate new and informative ALS models rapidly based on FUS/TLS mutations, we propose to use three parallel but complementary approaches to express normal or mutant FUS/TLS in transgenic mice. In the first approach, we will produce mice in which expression of FUS/TLS (wild type and two ALS mutants) is driven by native genomic regulatory elements. A novel aspect of our design will be the incorporation of conditional knockout capabilities that will allow us to selectively turn off the mutant gene expression to determine in which cell types the mutant proteins exert their most potent effects. In the second approach, we will generate mice in which expression of FUS/TLS transgenes is activated only after crossing with mice that express Cre recombinase in specific tissues. This strategy will allow the selection and breeding of founder animals even if the mutant gene is highly toxic. Furthermore, we can determine whether transgene expression causes motor neuron toxicity by cell autonomous or non-cell autonomous mechanisms. In the third approach, we will express wild type and mutant FUS/TLS in transgenic mice under temporal control using a tetracycline-inducible strategy. In the case of developmental or early postnatal toxicity of transgene expression, this approach will allow us to initiate or silence expression at different ages, thus enabling us to investigate the role of aging in this disease and the reversibility of this disease when the mutant gene is silenced. These studies will guide the development of therapies in the future. Together, these complementary approaches are likely to produce one or more animal models of ALS based on FUS/TLS mutations, making them available for us and the research community in general to study the mechanism of the disease and to develop new therapeutic strategies.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) is a devastating neurodegenerative condition in which the nerve cells in the brain and spinal cord that control the muscles die prematurely. Currently no truly effective treatments exist to slow the relentless course of the disease. This project will address the urgent need to develop informative mouse models of ALS that will i) accelerate the identification of novel treatment target(s) and ii) enable the testing of new therapeutic strategies to combat ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
5RC1NS068391-02
Application #
7937835
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (58))
Program Officer
Gubitz, Amelie
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$499,740
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Neurology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Kubat ├ľktem, Elif; Mruk, Karen; Chang, Joshua et al. (2016) Mutant SOD1 protein increases Nav1.3 channel excitability. J Biol Phys 42:351-70
Peters, Owen M; Ghasemi, Mehdi; Brown Jr, Robert H (2015) Emerging mechanisms of molecular pathology in ALS. J Clin Invest 125:1767-79
Tibshirani, Michael; Tradewell, Miranda L; Mattina, Katie R et al. (2015) Cytoplasmic sequestration of FUS/TLS associated with ALS alters histone marks through loss of nuclear protein arginine methyltransferase 1. Hum Mol Genet 24:773-86
Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C et al. (2014) ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation. Proc Natl Acad Sci U S A 111:1622-7
Convertini, Paolo; Zhang, Jiayu; de la Grange, Pierre et al. (2013) Genome wide array analysis indicates that an amyotrophic lateral sclerosis mutation of FUS causes an early increase of CAMK2N2 in vitro. Biochim Biophys Acta 1832:1129-35
Morfini, Gerardo A; Bosco, Daryl A; Brown, Hannah et al. (2013) Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS One 8:e65235
Teng, Yang D; Benn, Susanna C; Kalkanis, Steven N et al. (2012) Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis. Sci Transl Med 4:165ra164
Qiu, Linghua; Rivera-Perez, Jaime A; Xu, Zuoshang (2011) A non-specific effect associated with conditional transgene expression based on Cre-loxP strategy in mice. PLoS One 6:e18778
Ju, Shulin; Tardiff, Daniel F; Han, Haesun et al. (2011) A yeast model of FUS/TLS-dependent cytotoxicity. PLoS Biol 9:e1001052
Bosco, Daryl A; Lemay, Nathan; Ko, Hae Kyung et al. (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19:4160-75

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