The Role of the Terminal Complement Pathway in ALS


Principal Investigator: Scott R Barnum
Abstract: DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neuron disease that leads to degeneration of motor neurons in the cortex, brainstem and spinal cord resulting in progressive paralysis and ultimately death. The occurrence of ALS is largely sporadic (SALS), however approximately five to ten percent of cases are familial, associated with mutations in one of several genes including Cu,Zn SOD-1, Alsin, Senataxin, TDP-43 and FUS/TLS. There is currently no prophylactic therapy or cure for ALS and the only approved treatment, riluzole, extends survival only a few months and is considered ineffective. Given the lack of effective therapies and the estimated lifetime risk of developing SALS ranging from 1 in 400 to 1 in 1000, the need for disease biomarkers and disease-modifying therapies is critical. Neuroinflammation has received attention as a mechanism that participates in motor neuron loss in ALS, due in large part to the recognition of immune-mediated contributions to other neurodegenerative diseases, including multiple sclerosis, Alzheimer's and Parkinson's disease. The complement system, a major arm of the innate immune system, drives neuroinflammation along with other inflammatory mediators in most, if not all, central nervous system diseases and infections. There is growing evidence that complement contributes to neurodegeneration in ALS. Several studies have found evidence of complement activation and deposition in the spinal cord of ALS patients as well as elevated levels of complement activation fragments in cerebrospinal fluid (CSF) or serum. In addition, rodent models of ALS, have shown changes in complement gene expression and complement deposition in motor neurons and neuromuscular junctions in pre- and symptomatic stages of murine ALS. Nevertheless, the role of complement in the development and progression of ALS remains ill-defined. We have taken a systematic approach to address the role of complement in murine ALS by crossing SOD1G93A transgenic mice with mice deficient in C3 or C5, the two central proteins of the complement system. We observed a time-dependent deposition of C9 in the spinal cords of SOD1G93A mice suggesting that the membrane attack complex contributes to neurodegeneration in ALS. Furthermore, we found that female C5+/- x SOD1G93A mice survived significantly longer than the respective genders in SOD1G93A mice, an observation that correlates with the reduced C5 levels in female mice. We hypothesize that C5 plays a central role in the development and progression of ALS and will address this hypothesis by comparing the clinical and histological ALS phenotypes of both genders of mice that are SOD1G93A tg and deficient in C3, C5, C5aR or C9 to SOD1G93A mice. These studies will provide new information regarding the role of complement in ALS and potentially new therapeutic directions.
Funding Period: 2013-02-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Role of KSRP in control of type I interferon and cytokine expression
    Peter H King
    1 Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama
    J Interferon Cytokine Res 34:267-74. 2014

Detail Information


  1. pmc Role of KSRP in control of type I interferon and cytokine expression
    Peter H King
    1 Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama
    J Interferon Cytokine Res 34:267-74. 2014
    ..Understanding the role of KSRP in cytokine mRNA metabolism should identify promising targets for the modulation of immune and inflammatory responses. ..

Research Grants30

  1. Washington National Primate Research Center
    David M Anderson; Fiscal Year: 2013
    ..All lentivirus-infected primates are housed in ABSL2/3 containment facilities with appropriate biosafety procedures. The University of Washington, including the WaNPRC, is fully accredited by AAALAC International. ..
    Matthew Harms; Fiscal Year: 2013
    ..This work will provide key insight into the molecular basis of ALS and will immediately impact efforts aimed at therapeutic development for this untreatable disease. ..
    ERICA DANIELLE KOVAL; Fiscal Year: 2013
    ..If successful, the proposed experiments will expand our understanding of the role of microRNAs in neuroinflammation and may also help inform the development of a novel ALS therapeutic. ..
  4. Modeling Mutant Profilin 1 Toxicity and ALS in vivo
    Zuoshang Xu; Fiscal Year: 2013
    NEIL ALAN SHNEIDER; Fiscal Year: 2013
  6. 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. ..
  7. Defining the Role of TDP-43 in Neurodegenerative Disease Pathways
    IGA NATALIA WEGORZEWSKA; Fiscal Year: 2013
    ..Additionally, we will examine whether abnormalities in RNA processing plays a fundamental role in TDP-43 related ALS, in an effort to define new targets for therapeutic intervention in ALS. ..
  8. Study on Neurodegeneration Using TDP-43 Transgenic Rats
    Hongxia Zhou; Fiscal Year: 2013
    ..Proposed studies will not only develop desirable animal models for ALS research, but also would establish a foundation for developing ALS therapies targeting astrocytes or mutant TDP-43. ..
  9. Targeted investigation of tissue specific oxidative stress in the etiology of ALS
    Holly Van Remmen; Fiscal Year: 2013
  10. 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. ..
  11. Role of ABC efflux transporters in ALS
    Davide Trotti; Fiscal Year: 2013
    ..In this application we propose to study the regulation and role of these ABC transporters in ALS. Our ultimate goal is to understand the pathogenic mechanisms of ALS to improve the chances of success of pharmacotherapy for this disease. ..
  12. SOD1/Bcl-2 induced mitochondrial dysfunction in FALS and SALS.
    Piera Pasinelli; Fiscal Year: 2013
    ..Using ALS mouse models (with a genetic mutation) and cells derived from patients without a genetic link, we will study a potentially common mechanism of disease pathogenesis that targets the powerhouse of cells (mitochondria). ..
  13. Mechanisms of virus-induced injury in the brain and spinal cord
    Kenneth L Tyler; Fiscal Year: 2013
  14. Disease Mechanisms in Human Ubiquilinopathy
    Teepu Siddique; Fiscal Year: 2013
    ..The outcome of this project will also have important implications in the understanding of the pathogenesis and treatment of other neurodegenerative diseases. ..
  15. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  16. Fate specification of corticospinal neurons by cell autonomous signaling
    Paola Arlotta; Fiscal Year: 2013
    ..Here we propose to determine the molecular signals that instruct the birth of this clinically relevant neuron type, and to investigate the extent to which CSMN can be regenerated for therapeutic application. ..
  17. Investigation of post-translational modifications in WT SOD1 in sporadic ALS
    DARYL ANGELA BOSCO; Fiscal Year: 2013
    ..The goal of this proposal is to further test the hypothesis that altered modifications of WT SOD1 are implicated as causative factors in SALS. ..
  18. Investigation of TDP-43 Function and Toxicity in C. elegans
    Christopher D Link; Fiscal Year: 2013
    ..In this project we will use model systems to determine the functions of TDP-43 and how its deposition may cause neurodegeneration. ..
  19. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  20. Novel neurotrophic therapy in a mouse model of ALS
    Alpaslan Dedeoglu; Fiscal Year: 2013
    ..The novel studies we propose will produce data to improve our understanding of disease mechanisms and test the beneficial effects of 7,8-DHF in ALS. ..