Epigenetic mechanisms of TDP43-mediated neurodegeneration

Summary

Principal Investigator: Amit Berson
Abstract: DESCRIPTION (provided by applicant): Epigenetic chromatin modifications such as histone methylation and acetylation are emerging as prominent regulators of human development, disease and aging. Although epigenetic modifications have been shown to be critical for neuronal function, the roles that such modifications play in maintenance of the nervous system and their contribution to neurodegenerative diseases remain largely unknown. To address this fundamental question, we recently performed an in-vivo RNAi screen for epigenetic modifiers of neurodegeneration in Drosophila, a powerful genetically amendable animal model. We began our analysis with an established model of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These devastating diseases are characterized by the abnormal cytoplasmic accumulation of TDP-43, an RNA and DNA binding protein. Mutations in the TDP-43 coding gene (TARDBP) are found in rare forms of FTD and ALS, providing additional genetic evidence for its causal involvement. Thus, expression of TDP-43 in the Drosophila nervous system provides a model for TDP-43 toxicity associated with FTD/ALS. By knocking down the expression of over 80 genes involved in various aspects of histone modifications and chromatin remodeling, we found that several factors, all of which impact a single modification (trimethylation of histone 3 at lysine 4 (H3K4me3)), robustly modulate toxicity of TDP-43 in Drosophila, but not that of other neurodegeneration-related proteins. These findings and subsequent experiments established that reducing the global levels of H3K4me3 enhances TDP-43 toxicity, whereas increasing H3K4me3 levels mitigates TDP-43 toxicity. Launching from this discovery, we will use Drosophila and human patient tissue to define the mechanisms by which this histone methylation mark affects FTD and ALS disease progression. First, rigorous controls in Drosophila will be performed, and the effects of histone methylation on toxicity of oter FTD- and ALS-associated genes and mutations will be examined. Second, using a recently developed in- vivo, cell type-specific chromatin immunoprecipitation and deep-sequencing (ChIP-Seq) technique, chromatin landscape alterations induced by TDP-43 will be characterized. Co-IP assays will determine if any factor known to bind or affect H3K4me3, physically interacts with TDP-43. Third, the human disease relevance of these findings will be determined using post-mortem brain samples from FTD and ALS patients and controls. This combination of in-vivo studies, cell-type specific analyses and next generation chromatin investigations in animal models and human disease samples will provide an exceptional opportunity to uncover the epigenetic mechanisms underlying these incurable diseases. Our promising preliminary findings demonstrate the timely nature of the proposed study and indicate that this work will provide fundamental insight into the biology of neurodegenerative diseases and the foundation for new therapeutic approaches.
Funding Period: 2013-09-01 - 2016-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
    Rama Natarajan; Fiscal Year: 2013
    ..The results can increase our understanding of Ang II actions, and identify new targets that might be developed as clinical therapies for CVDs such as hypertension and atherosclerosis. ..
  2. Regulating fibrosis and muscle growth in the muscular dystrophies
    Elizabeth M McNally; Fiscal Year: 2013
    ..Core B will provide histopathological assessment of muscular dystrophy after genetic manipulation and treatments, and Core C will perform functional analysis in vivo and provide support to Core B. ..
  3. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
    ....
  4. NK Cells, Their Receptors and Unrelated Donor Transplant
    Jeffrey S Miller; Fiscal Year: 2013
    ..The program also promises to change practice of allogeneic transplantation, to the greater benefit of patients with advanced leukemia. ..
  5. Developmental Trajectories of Negative Symptoms in Schizophrenia
    Raquel E Gur; Fiscal Year: 2013
    ..In addition to advancing its scientific agenda, the Center will be an educational resource for faculty, fellows, residents, graduate and undergraduate students. It will also be a clinical and educational. ..
  6. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..
  7. Molecular Pathogenesis of the Hamartoma Syndromes
    David J Kwiatkowski; Fiscal Year: 2013
    ..abstract_text> ..
  8. Mechanisms of Chromatin Transcriptional Regulation
    MICHAEL GUY POIRIER; Fiscal Year: 2013
    ..These studies will provide a foundation for understanding the mechanisms and functional interactions behind chromatin transcriptional regulation and the misregulation of numerous oncogenes. ..
  9. Identifying the molecular mechanisms of transgenerational epigenetic inheritance
    Eric L Greer; Fiscal Year: 2013
    ..This research funding will help launch an independent research laboratory to study how epigenetic information regulates longevity. ..
  10. Dopaminergic Epigenomes from Human Brain
    Michael J Bannon; Fiscal Year: 2013
    ....
  11. HEALTHY AGING AND SENILE DEMENTIA
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
  12. Epigenetic Changes associated with Neurodegenerative Diseases
    FREDERICK B JOHNSON; Fiscal Year: 2013
    ..In the broader scientific and medical communities, this effort will promote discoveries of epigenetic mechanisms of ND to provide the foundation for new insights and novel clinical approaches to treat ND. ) ..
  13. 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. ..
  14. UCLA Alzheimer's Disease Research Center
    David B Teplow; Fiscal Year: 2013
    ..Innovations in advancing research are proposed in each Core of this proposal. Each core has responded to criticisms and recommendations from the 2008 review in this renewal application. ..
  15. Epigenome Mapping in Cortical Interneurons
    Schahram Akbarian; Fiscal Year: 2013
    ....
  16. Novel Epigenetic Roles of the Proteasome in Long-term Synaptic Plasticity
    SVITLANA BACH; Fiscal Year: 2013
    ....
  17. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  18. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  19. Epigenetic Regulation of Heterochromatin Condensation in Huntington's Disease
    Hoon Ryu; Fiscal Year: 2013
    ..Considering a fact that epigenetic regulation is a strong candidate method from a therapeutic perspective, our mechanistic study will contirbute to finding of the novel therapeutic target and epigenetic biomarker in HD. ..
  20. Histone Chaperones and Acetyltransferases in Chromatin Transitions
    Jennifer K Nyborg; Fiscal Year: 2013
    ..abstract_text> ..
  21. 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. ..
  22. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..