Protein interactions with CADASIL-mutants of Notch3

Summary

Principal Investigator: Michael M Wang
Abstract: [unreadable] DESCRIPTION (provided by applicant): Stroke and vascular dementia are prevalent diseases which are both caused by multiple factors, including genetic susceptibility. In large part, the genetics of these disorders is complex. However, in families with CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), premature stroke and vascular dementia are caused by defects in the Notch3 gene. Our broad goal is to identify the molecular pathways governing the pathogenesis of CADASIL, which will help shed light on more common forms of stroke and dementia. We have proposed that mutant Notch3, expressed in arterial smooth muscle, assumes structural changes, allowing interactions with proteins that foster protein aggregation and toxic gain of function. In this study, we will identify and characterize proteins which interact with Notch3. In preliminary experiments, we have identified vascular gene products which interact with the Notch3 extracellular domain (the site of all CADASIL mutations) in yeast. We plan to perform exploratory experiments to characterize the potential role of these PUtative NotCH3 interactors (PUNCH) in CADASIL. In Specific Aim 1, we will demonstrate that the PUNCH proteins physically bind to Notch3 in mammalian cells; we will determine if coexpression of PUNCH proteins (with Notch3) functionally causes cell death or increases the levels of Notch3 in transfected cell lines; these features are seen pathologically in arteries of CADASIL patients. In Specific Aim 2, we will use novel transgenic mice expressing epitope tagged Notch3 extracellular domain to determine whether PUNCH and Notch3 interact in vivo; we will also examine transgenic mouse and CADASIL tissues for pathological accumulation of PUNCH. Completion of these Aims will confirm the in vitro function of PUNCH proteins in the context of Notch3 mutations and may identify new markers and biochemical pathways specific for this disease. The discovery of new Notch3 interacting proteins will also faciliate the production of new cellular and transgenic models of stroke and vascular dementia, which is one of the goals of the RFA to which we respond. In lay language, this application is designed to investigate the molecules involved in a disease, CADASIL that causes stroke and dementia. An understanding of CADASIL may provide clues to designing better treatments and prevention strategies for stroke and dementia. What is learned from this study may also provide information that will be useful for the treatment of other vascular diseases. Stroke and vascular dementia are common and debilitating diseases which are both caused by multiple factors, including genetic susceptibility. We propose to study a genetic cause of stroke and vascular dementia: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Understanding CADASIL may provide clues to designing better treatments and prevention strategies for stroke and dementia. [unreadable] [unreadable] [unreadable]
Funding Period: 2007-02-01 - 2010-01-31
more information: NIH RePORT

Top Publications

  1. pmc Localization of blood proteins thrombospondin1 and ADAMTS13 to cerebral corpora amylacea
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109 5622, USA
    Neuropathology 29:664-71. 2009
  2. ncbi ABO blood antigens define human cerebral endothelial diversity
    Michael M Wang
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
    Neuroreport 24:79-83. 2013
  3. pmc Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
    Hairong Dong
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Brain Res 1456:64-71. 2012
  4. pmc Notch signaling and Notch signaling modifiers
    Michael M Wang
    Neurology Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
    Int J Biochem Cell Biol 43:1550-62. 2011
  5. pmc Ischemic stroke selectively inhibits REM sleep of rats
    Samreen Ahmed
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Exp Neurol 232:168-75. 2011
  6. pmc Stromal LRP1 in lung adenocarcinoma predicts clinical outcome
    He Meng
    Departments of Neurology, University of Michigan and Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan 48109, USA
    Clin Cancer Res 17:2426-33. 2011
  7. ncbi Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Arch Neurol 68:1584-6. 2011
  8. pmc Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109 5622, USA
    J Biol Chem 285:23047-55. 2010
  9. pmc Thrombospondin 2 potentiates notch3/jagged1 signaling
    He Meng
    Department of Neurology and Molecular, University of Michigan, Ann Arbor, Michigan 48109 5622, USA
    J Biol Chem 284:7866-74. 2009
  10. pmc Lysosome-dependent degradation of Notch3
    Lijun Jia
    Departments of Neurology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 0622, USA
    Int J Biochem Cell Biol 41:2594-8. 2009

Detail Information

Publications11

  1. pmc Localization of blood proteins thrombospondin1 and ADAMTS13 to cerebral corpora amylacea
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109 5622, USA
    Neuropathology 29:664-71. 2009
    ..We speculate that CA could result from a conglomeration of interacting proteins from degenerating neurons and from extravasated blood elements released after transient breakdown of the blood-brain barrier...
  2. ncbi ABO blood antigens define human cerebral endothelial diversity
    Michael M Wang
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
    Neuroreport 24:79-83. 2013
    ..Future studies are warranted to determine whether differences in capillary permeability and cerebral autoregulation vary over short distances within the brain...
  3. pmc Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
    Hairong Dong
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Brain Res 1456:64-71. 2012
    ..These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL...
  4. pmc Notch signaling and Notch signaling modifiers
    Michael M Wang
    Neurology Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
    Int J Biochem Cell Biol 43:1550-62. 2011
    ..Here, I review current concepts in Notch signaling, with a focus on work from the last decade elucidating novel extracellular proteins that up- or down-regulate signal potency...
  5. pmc Ischemic stroke selectively inhibits REM sleep of rats
    Samreen Ahmed
    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Exp Neurol 232:168-75. 2011
    ..Further experiments using this experimental model should be performed to investigate the mechanisms and consequences of REM suppression after stroke...
  6. pmc Stromal LRP1 in lung adenocarcinoma predicts clinical outcome
    He Meng
    Departments of Neurology, University of Michigan and Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan 48109, USA
    Clin Cancer Res 17:2426-33. 2011
    ..It is expressed in numerous cancers, but its role in lung cancer has not been characterized. Here, we investigate the relationship between LRP1 and lung cancer...
  7. ncbi Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Arch Neurol 68:1584-6. 2011
    ....
  8. pmc Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109 5622, USA
    J Biol Chem 285:23047-55. 2010
    ..Our data suggest that LRP1 and TSP2 stimulate Notch activity by driving trans-endocytosis of the Notch ectodomain into the signal-sending cell and demonstrate a novel, non-cell autonomous function of LRP1 in cell-cell signaling...
  9. pmc Thrombospondin 2 potentiates notch3/jagged1 signaling
    He Meng
    Department of Neurology and Molecular, University of Michigan, Ann Arbor, Michigan 48109 5622, USA
    J Biol Chem 284:7866-74. 2009
    ..These studies demonstrate that the diverse functions of TSP2 may also include a role as an intermediary protein that facilitates transcellular receptor-ligand interactions...
  10. pmc Lysosome-dependent degradation of Notch3
    Lijun Jia
    Departments of Neurology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109 0622, USA
    Int J Biochem Cell Biol 41:2594-8. 2009
    ..In sum, our experiments demonstrate a critical role for lysosomes in the degradation of Notch3, which distinguishes it from Notch1 and Notch4...
  11. pmc Collagen represses canonical Notch signaling and binds to Notch ectodomain
    XiaoJie Zhang
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Int J Biochem Cell Biol 45:1274-80. 2013
    ..In addition, type I collagen also inhibited Notch signaling and bound to Notch and Jagged. We conclude that type IV and type I collagen repress canonical Notch signaling to alter expression of Notch target genes...