Cellular and Animal Models of FUS Mutations in ALS


Principal Investigator: Eric J Huang
Abstract: DESCRIPTION (provided by applicant): This R21 application is prepared in response to PA-10-138, "Development of Animal Models and Related Biological Materials For Research". In this application, we propose to establish both cellular and animal models that will allow us to characterize the mechanism of FUS/TLS mutations. The FUS/TLS locus on human chromosome 16 is originally identified to encode an oncogene implicated in malignant liposarcoma and myeloid leukemia. More recent evidence shows that mutations in FUS/TLS are found in familial cases of amyotrophic lateral sclerosis (ALS). These results indicate that further investigations to the mechanisms of FUS/TLS gene will have profound impacts on many disciplines in biomedical research, including cancer biology, neurodegeneration, aging, and mental health. Although most mutations are found in the highly conserved C-terminal region of the FUS protein, the precise pathogenic mechanisms for these mutations have not been fully elucidated. Among the FUS mutations, the most common form in adult ALS patients is the R521C mutation. In addition, our recent study indicates that the P525L mutation in FUS leads to a more aggressive and rapidly progressive form of ALS in young patients. Currently, it is unclear how FUS-R521C and FUS-P525L cause neuronal degeneration, or why FUS-P525L tends to affect younger patients. Our recent data, however, indicated that the spinal motor neurons in patients with P525L mutation show mislocalization of mutant FUS proteins in neuronal cytoplasm with abnormal FUS protein aggregates that are associated with markedly disorganized intracellular organelles, including endoplasmic reticulum (ER) and mitochondria. These results lead us to hypothesize that mutant FUS proteins dominantly inhibit normal RNA and protein synthesis and thereby suppressing neuronal functions and survival. Our objectives are to further investigate the mechanisms of mutant FUS proteins in neuronal degeneration using both primary neurons and transgenic mice. Since synaptic degeneration plays a central role in neurodegenerative diseases, we believe that the establishment of these models will contribute to understanding of the mutant FUS proteins in the development and maintenance of synaptic connectivity of motor neurons within the spinal cord and at the neuromuscular junction (NMJ). We propose two specific aims to achieve these goals. In Aim 1, we will characterize the mechanisms by which FUS-R521C and FUS-P525L mutant proteins affect synaptic degeneration and cell death in primary neurons. In Aim 2, we propose to characterize if mice expressing FUS-R521C or FUS-P525L develop motor behavioral phenotype and motor neuron pathology similar to patients with corresponding mutations. We believe that the establishment of these models will have important contributions to the missions of many institutions at NIH, and fulfills the criteria of "high rewards and high impacts" for the R21 funding mechanism. Once available, these models will serve as novel platforms to identify new therapeutic targets for diseases caused by FUS/TLS mutations.
Funding Period: 2012-07-15 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease
    Keith A Vossel
    Department of Neurology, University of California, San Francisco, CA, USA
    Neurocase 19:295-301. 2013

Detail Information


  1. pmc ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease
    Keith A Vossel
    Department of Neurology, University of California, San Francisco, CA, USA
    Neurocase 19:295-301. 2013
    ..Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43...

Research Grants30

  1. Mechanism of FUS Mutations in the Pathogenesis of ALS
    Eric J Huang; Fiscal Year: 2013
  2. Epigenetic mechanisms relevant to the pathogenesis of ALS
    Neil W Kowall; Fiscal Year: 2013
    ..The urgent need for such studies is highlighted by the prospect that hundreds of thousands of future veterans may be at increased risk for this devastating disease. ..
  3. Alzheimer's Disease Research Center at Columbia University
    Scott A Small; Fiscal Year: 2013
    ..HIPAA compliant data organization and statistical consulting services are provided under the ADRC to the research community at Columbia and external to it. ..
    Kenneth H Cowan; Fiscal Year: 2013
  5. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  6. Modeling Mutant Profilin 1 Toxicity and ALS in vivo
    Zuoshang Xu; Fiscal Year: 2013
  7. High Throughput Screening for Compounds to Mitigate Toxicity of FUS/TLS &SOD1
    Robert H Brown; Fiscal Year: 2013
    ..Moreover, it is conceivable that the compounds discovered in these studies will prove beneficial in neurodegenerative conditions other than ALS alone. ..
  8. Defects of mitochondrial dynamics in ALS
    Giovanni Manfredi; Fiscal Year: 2013
    ..abstract_text> ..
  9. Tissue injury and inflammation in MS (P50)
    Bruce D Trapp; Fiscal Year: 2013
    ..abstract_text> ..
  10. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  11. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  12. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  13. The Pathogenesis of Facioscapulohumeral Muscular Dystrophy
    Stephen J Tapscott; Fiscal Year: 2013
    ..Together, these studies combine genetic, epigenetic, transcriptional and developmental approaches to defining the molecular deficits that cause FSHD and will provide a new basis for developing therapies. ..
  14. Investigating a Toxic Gain-of-Interaction Between FUS/TLS &Stress Granules
    DARYL ANGELA BOSCO; Fiscal Year: 2013
    ..These studies have the potential to reveal stress granules as biomarkers of ALS. ..
  15. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
    ..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
  16. Role of FUS in ALS
    Haining Zhu; Fiscal Year: 2013
    ..The findings are expected to provide critical insights into the mechanisms by which FUS mutations perturb the RNA processing pathways and ultimately lead to the disease. ..
  17. New Approaches to Dementia Heterogeneity
    Bruce L Miller; Fiscal Year: 2013
    ..Finally, we will create ideal data management approaches for neurodegenerative conditions that will be shared with other ADRCs, beginning with UC-Davis. ..
  18. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  19. TBI-Induced Cerebral Metabolic Depression and Recovery
    David A Hovda; Fiscal Year: 2013
    ..This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support. ..
  20. The role of mir-17~92 cluster in motor neuron degeneration
    Hynek Wichterle; Fiscal Year: 2013
    ..Understanding miRNA controlled cell type specific survival pathways might provide new targets for slowing down or arresting progression of motor neuron loss in motor neuron diseases. ..