Genomes and Genes
ALS therapies and genomics for mutant TDP-43 and TLS/FUS
Principal Investigator: Don W Cleveland
Abstract: This application addresses two Broad Challenge areas (15) Translational Science, including specific Challenge Topics 15-NS-104 (Early-stage therapy development) and 15-NS-103 (Demonstration of "proof-of-concept") and Broad Challenge area (08) Genomics, specific Challenge Topic 03-NS-101 (Cross-disease research to identify mechanisms common to Mendelian disorders of low incidence and genetically complex, high incidence disorders). Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder in which premature loss of upper and lower motor neurons leads to fatal paralysis with a typical disease course of one to five years. While most efforts to understand ALS pathogenesis over the last 15 years have focused on disease caused by mutation in the ubiquitously expressed superoxide dismutase (representing ~2% of all instances of ALS), during the past 14 months, a paradigm shift in understanding ALS has been initiated by discovery that mutations in two strikingly similar DNA/RNA binding proteins, TAR DNA-binding protein (TDP-43) and Fused in sarcoma (FUS/TLS), are also primary causes of ALS. In the normal context, both proteins have been linked to RNA transcription and alternative RNA splicing (FUS/TLS is an integral component of the spliceosome). This has raised the provocative possibility that alterations of RNA metabolism, especially errors of alternative RNA splicing, play a crucial role in ALS pathogenesis. With the further realization that TDP-43-containing cytoplasmic inclusions are found in the vast majority of ALS sporadic patients and in several other neurodegenerative diseases including Frontal Temporal Dementia (FTD), errors in TDP-43 may be central to understanding disease mechanism not just in ALS by also other neurodegenerative disorders. Here, we propose 1) to combine transgenic and gene- targeting approaches to develop new mouse models for TDP-43 and FUS/TLS mediated ALS and 2) to utilize newly developed methodologies linked to high-throughput sequencing to determine the role of TDP-43 and FUS/TLS in the regulation of RNA metabolism as a means to understand how their alterations underlie pathogenesis and to identify new targets for therapy development. PUBLIC HEALTH RELEVANCE: Over the last 14 months, a paradigm shift in understanding what goes wrong in the fatal motor neuron disease Amyotrophic Lateral Sclerosis has been initiated by the discoveries that mutations in a pair of RNA binding proteins (TDP-43 and FUS/TLS) are primary causes of the disease. Through construction and analysis of mice that are genetic mimics of these instances of inherited ALS, how these mutations cause premature death of the motor neurons will be identified. New, very high through put DNA/RNA sequencing methods will be used to identify genes whose expression is altered by the mutations, thereby identifying new targets and approaches for devising a successful therapy for ALS.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT
- Rethinking ALS: the FUS about TDP-43Clotilde Lagier-Tourenne
Department of Cellular and Molecular Medicine, University of California San Diego, Ludwig Institute for Cancer Research, La Jolla, CA 92093 0670, USA
Cell 136:1001-4. 2009..TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as a key event in ALS pathogenesis...
- ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43Eveline S Arnold
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Proc Natl Acad Sci U S A 110:E736-45. 2013..Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage...
- ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLSShuo Chien Ling
Ludwig Institute for Cancer Research and Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093 0670, USA
Proc Natl Acad Sci U S A 107:13318-23. 2010..Taken together, abnormal stability of mutant TDP-43 and its enhanced binding to normal FUS/TLS imply a convergence of pathogenic pathways from mutant TDP-43 and FUS/TLS in ALS...
- Understanding the role of TDP-43 and FUS/TLS in ALS and beyondSandrine Da Cruz
Ludwig Institute and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093 0670, United States
Curr Opin Neurobiol 21:904-19. 2011....