Role of Proteasome Inhibition in the Pathogenesis of CADASIL

Summary

Principal Investigator: Michael M Wang
Abstract: 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. The central hypothesis is that mutant NotchS, expressed in arterial smooth muscle, triggers a series of cellular changes that result in inhibition of the proteasome. The proteasome is essential for the degradation of proteins via the ubiquitin proteasome system and has been implicated in several neurodegenerative disorders. We propose that inhibition of the proteasome in vascular smooth muscle causes cell toxicity and is linked to the breakdown of cell-cell contacts and accumulation of Notch3 protein, two pathological features of CADASIL. In support of this concept, we present preliminary data showing that Notch3 specifically interacts with a subunit of the 26S proteasome. In addition, we demonstrate evidence that proteasome inhibition is increased in cells expressing mutant Notch3. Finally, proteasome inhibition in cultured smooth muscle cells causes cell-cell separation and cell death, two features seen in CADASIL tissues. In Specific Aim 1, we will characterize whether mutant Notch3 directly inhibits proteasomes and whether mutant Notch3 over-expression leads to proteasome inhibition in cell culture and in arteries of transgenic animals. In Aim 2, we will determine whether proteasome inhibition leads to cell-cell contact disruption and Notch3 protein accumulation in culture and in vivo. Finally, in Aim 3, we will investigate whether cell death due to proteasome inhibition is exacerbated by Notch3 mutations and by cell-cell contact disruption. These experiments will support a CADASIL pathway involving proteasomal inhibition and may have implications for the pathogenesis of other vascular and proteasome-linked diseases. 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.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Genetics of ischemic stroke: future clinical applications
    Michael M Wang
    Department of Neurology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA
    Semin Neurol 26:523-30. 2006
  2. 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
  3. pmc Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL
    Hairong Dong
    Department of Neurology, University of Michigan, 7629 Med Sci II 5622, 1137 Catherine St, Ann Arbor, MI 48109, USA
    Stroke 44:1456-8. 2013
  4. pmc Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex
    Ryan A Frieler
    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Am Heart Assoc 1:e002584. 2012
  5. 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
  6. pmc Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e44964. 2012
  7. pmc Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression
    XiaoJie Zhang
    Departments of Neurology X Z, H M, M M W, Molecular and Integrative, Physiology J S, M M W, and Pathology M B, University of Michigan Medical School, Ann Arbor, MI 48109 Department of Neurology, Veterans Administration Ann Arbor Healthcare, System, Ann Arbor, MI 48105 M M W Institute for Neuropathology, Universitatsspital, CH 8091 Zurich E J R Department of Pathology and Center for Alzheimer s Disease and Related Disorders, Southern Illinois University School of Medicine, Springfield, IL 62794 B E M Departments of Pathology M B S L, Neurology B B W, and Public Health Sciences B B W, University of Virginia, Charlottesville, VA 22908
    Transl Stroke Res 3:138-45. 2012
  8. pmc Von Willebrand factor inhibits mature smooth muscle gene expression through impairment of Notch signaling
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 8:e75808. 2013
  9. pmc Jagged1 expression regulated by Notch3 and Wnt/β-catenin signaling pathways in ovarian cancer
    Xu Chen
    Department of Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
    Oncotarget 1:210-8. 2010
  10. pmc Posttranslational regulation of TPH1 is responsible for the nightly surge of 5-HT output in the rat pineal gland
    Zheping Huang
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
    J Pineal Res 45:506-14. 2008

Scientific Experts

  • Michael M Wang
  • Pamela J Lein
  • He Meng
  • XiaoJie Zhang
  • Soo Jung Lee
  • Mila Blaivas
  • Hairong Dong
  • Ryan A Frieler
  • Yangdong He
  • Genggeng Yu
  • Samreen Ahmed
  • Jimo Borjigin
  • Tiecheng Liu
  • Stefan Berger
  • Richard M Mortensen
  • Daniel A Lawrence
  • Michelle M Garred
  • Guohua Xi
  • Xu Chen
  • Lijun Jia
  • Asamanja Chattoraj
  • Zheping Huang
  • Haixia Ding
  • Kelly Young
  • Paul J Christensen
  • Y Eugene Chen
  • David J Pinsky
  • Jessica Schwartz
  • Michael G Usher
  • Enming J Su
  • Jessica J Ray
  • Elisabeth J Rushing
  • Bradford B Worrall
  • Brian E Moore
  • Sai P Ramnarayanan
  • Igor Prudovsky
  • M Beatriz S Lopes
  • Xin Guo
  • David G Beer
  • Ya Hua
  • Wenquan Liu
  • Mark R Opp
  • Dafydd G Thomas
  • Blair C Sutton
  • Christina A Harrington
  • Gunther Schutz
  • Richard F Keep
  • Omar Elmadhoun
  • Guoan Chen
  • Zhuwen Wang
  • Thomas J Giordano
  • Sheng Zhong Duan
  • Alexander Stoeck
  • Tian Li Wang
  • Dudley K Strickland
  • Ie Ming Shih
  • Kurt D Hankenson
  • Yanmei Zhang
  • Yezi Peng
  • Rushdee Hasan
  • Lijun Wang
  • Samantha L Zhang
  • Christina Chae
  • Theresa M Lee
  • Xing Sun
  • Jie Deng

Detail Information

Publications27

  1. ncbi Genetics of ischemic stroke: future clinical applications
    Michael M Wang
    Department of Neurology and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA
    Semin Neurol 26:523-30. 2006
    ..We review the studies of these genes and discuss the future potential applications of genetic markers on the management of ischemic stroke patients...
  2. 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...
  3. pmc Advanced intimal hyperplasia without luminal narrowing of leptomeningeal arteries in CADASIL
    Hairong Dong
    Department of Neurology, University of Michigan, 7629 Med Sci II 5622, 1137 Catherine St, Ann Arbor, MI 48109, USA
    Stroke 44:1456-8. 2013
    ..We quantified substructure and diameter of leptomeningeal arteries in CADASIL compared with age-matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry...
  4. pmc Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex
    Ryan A Frieler
    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Am Heart Assoc 1:e002584. 2012
    ..In this study, we explore both model- and sex-specific actions of myeloid MR during ischemic stroke...
  5. 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...
  6. pmc Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e44964. 2012
    ..We conclude that CADASIL mutants of NOTCH3 complex with NOTCH1, 3, and 4, slow NOTCH3 clearance, and that overexpressed wild type and mutant NOTCH3 protein interfere with key NOTCH-mediated functions in smooth muscle cells...
  7. pmc Von Willebrand Factor permeates small vessels in CADASIL and inhibits smooth muscle gene expression
    XiaoJie Zhang
    Departments of Neurology X Z, H M, M M W, Molecular and Integrative, Physiology J S, M M W, and Pathology M B, University of Michigan Medical School, Ann Arbor, MI 48109 Department of Neurology, Veterans Administration Ann Arbor Healthcare, System, Ann Arbor, MI 48105 M M W Institute for Neuropathology, Universitatsspital, CH 8091 Zurich E J R Department of Pathology and Center for Alzheimer s Disease and Related Disorders, Southern Illinois University School of Medicine, Springfield, IL 62794 B E M Departments of Pathology M B S L, Neurology B B W, and Public Health Sciences B B W, University of Virginia, Charlottesville, VA 22908
    Transl Stroke Res 3:138-45. 2012
    ..We tested whether endothelial von Willebrand factor (vWF) accumulates in CADASIL vessels and whether exposure of smooth muscle cells to vWF alters the expression of smooth muscle gene expression...
  8. pmc Von Willebrand factor inhibits mature smooth muscle gene expression through impairment of Notch signaling
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 8:e75808. 2013
    ..In sum, these studies demonstrate vWF in the vessel wall as a common feature of cerebral SVD; furthermore, we provide a plausible mechanism by which non-hemostatic vWF may play a novel role in the promotion of vascular disease. ..
  9. pmc Jagged1 expression regulated by Notch3 and Wnt/β-catenin signaling pathways in ovarian cancer
    Xu Chen
    Department of Gynecology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
    Oncotarget 1:210-8. 2010
    ..In addition, Wnt/β-catenin pathway activation also up-regulated Jagged1. Both mechanisms may sustain Notch3 signaling in ovarian cancer cells and contribute to the pathogenesis of ovarian carcinoma...
  10. pmc Posttranslational regulation of TPH1 is responsible for the nightly surge of 5-HT output in the rat pineal gland
    Zheping Huang
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
    J Pineal Res 45:506-14. 2008
    ..These data support the model that increased nocturnal 5-HT synthesis in the pineal gland is mediated by the phosphorylation of TPH1 at the serine 58, which elevates the TPH1 protein content and activity at night...
  11. 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...
  12. pmc p150/glued modifies nuclear estrogen receptor function
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Mol Endocrinol 23:620-9. 2009
    ..Our results suggest that p150/glued modulates estrogen sensitivity in cells through nuclear mechanisms...
  13. pmc Nuclear contrast angiography: a simple method for morphological characterization of cerebral arteries
    He Meng
    Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109 5622, USA
    Brain Res 1261:75-81. 2009
    ..This method should be useful in studies of stroke and cerebral arteriogenesis, which require the accurate assessment of both arterial diameters and endothelial cell density...
  14. 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...
  15. pmc Posttranscriptional regulation of pineal melatonin synthesis in Octodon degus
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    J Pineal Res 47:75-81. 2009
    ..These data suggest that Octodon degus may provide an ideal model system for laboratory investigation of mechanisms of melatonin synthesis and secretion in diurnal mammals...
  16. 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...
  17. 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
    ....
  18. 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...
  19. 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...
  20. pmc Transcriptional responses of cultured rat sympathetic neurons during BMP-7-induced dendritic growth
    Michelle M Garred
    Gene Microarray Shared Resource, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 6:e21754. 2011
    ..We used this culture system to examine differential gene expression patterns in naïve vs. BMP-treated sympathetic neurons in order to identify candidate genes involved in regulation of primary dendritogenesis...
  21. ncbi Hemoglobin expression in neurons and glia after intracerebral hemorrhage
    Yangdong He
    Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA
    Acta Neurochir Suppl 111:133-7. 2011
    ..These results indicate that ICH increases HbA and HbB expression in neurons and glia cells, and that heme and iron may be important factors in inducing endogenous Hb expression after ICH...
  22. 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...
  23. pmc Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia
    Ryan A Frieler
    Department of Internal Medicine, Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mich 48109, USA
    Stroke 42:179-85. 2011
    ..In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout mice...
  24. 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...
  25. 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...