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Apoptosis and Diseases

Apoptosis and Diseases. Contents. Concept Major pathways Key molecule s Apoptosis-related diseases Insufficient apoptosis in diseases Excessive apoptosis in diseases Coexistence of insufficient and excessive apoptosis in diseases Principles of treatment. History of Cell Death Research.

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Apoptosis and Diseases

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  1. Apoptosis and Diseases

  2. Contents • Concept • Major pathways • Key molecules • Apoptosis-related diseases • Insufficient apoptosis in diseases • Excessive apoptosis in diseases • Coexistence of insufficient and excessive apoptosis in diseases • Principles of treatment

  3. History of Cell Death Research

  4. Using C. elegan as a model

  5. Apoptosis or Programmed Cell Death pre-programed, cascade events ATP, gene expression A highly regulated active cell death characterized by cell shrinkage and nuclear condensation. Morphology opposite tonecrosis What is the difference of programmed cell death and apoptosis?

  6. Apoptosis and Necrosis

  7. Apoptotic Process Stimulatory Factors Inhibitory Factors Physiological, FasL; Pathological, glutamate, free radicals; therapeutical, herb. Initiation Physiological, e.g., growth factors, estrogen; virus; chemicals. Regulation Execution Conserved Phagocytosis

  8. Conserved apoptotic paradigms in C. elegans, Drosophia, and mammals

  9. Apoptotic Pathways • Death receptor-mediated apoptotic pathway • Mitochondria-mediated apoptotic pathway • Nuclear-mediated apoptotic pathway

  10. Apoptotic Pathways death-inducing signaling complex Fas-associating protein with death domain

  11. Mitochondrial Membrane Permeabilization (MMP) in Apoptotic Process

  12. ER and Apoptosis

  13. Cross-talking among Organelles and Molecules in Apoptosis

  14. Executors • 1. Activation of endonuclease • 2.Activation of caspases DNA ladder Collapse of cell and nucleus

  15. Role of Endonuclease H1 180-200 bp Endonuclease Zn2+ Ca2+ Mg2+

  16. Role of Caspases (p21-activated kinase 2) (Ste20-related kinase) (Focal adhesion kinase)

  17. Phosphatidylserine (PS) receptor (PSR) acts as a ‘tickle’ receptor for uptake of apoptotic cells

  18. Key Molecules • Caspases: Caspase-3,Caspase-8,Caspase-9, etc. 2. Bcl-2 family： anti-apoptotic: Bcl-2 (Bcell lymphoma/leukemia), Bcl-XL pro-apoptotic: Bax, Bad 3. Others: Apaf-1(apoptosis activating factor-1), cytochrome C, IAPs, p53, etc.

  19. Table 1. Caspase-deficient miceKnockout Phenotype Caspase-1 Viable; impaired processing of IL-1; resistant to endotoxic shock. Caspase-2 Viable; excess numbers of female germ cells; oocytes resistant to chemotherapeutic drugs; B lymphoblasts resistant to granzyme B; accelerated death of facial neurons during development and of sympathetic neurons deprived of NGF. Caspase-3 Lethality at 3–5 weeks of age; defective neuronal apoptosis; T cells resistant to antigen-induced death; abnormal apoptotic morphology in dying cells. Caspase-8 Lethality around E12.5; hyperemia and abnormal heart muscle development; MEFs resistant to TNF, Fas and DR3 but sensitive to UV irradiation, etoposide, staurosporine, serum deprivation. Caspase-9 Perinatal lethal; impaired neuronal apoptosis; ES cells, MEFs and thymocytes generally resistant to intrinsic death stimuli such as DNA damage, though resistance depends on cell type. Caspase-11 Viable; impaired processing of caspase-1, IL-1; resistant to endotoxic shock. Caspase-12 Viable; embryonic fibroblasts are resistant to ER stress.

  20. Apoptosis-related Diseases

  21. Balance of Growth and Apoptosis Apoptosis Growth

  22. Insufficient Apoptosis in Diseases Autoimmune disease, Tumor, virus infection, etc Proliferation Apoptosis

  23. (1) Tumor Pathogenesis for tumor: stimulated cell proliferation inhibited cell apoptosis Cell survival > cell death in diseased tissue Etiologically, cell apoptosis is actually one of the natural anti-carcinogenic mechanisms

  24. (2) Autoimmune diseases The lesion is caused by attack of auto-antibody or sensitized T cell to self-antigen. Normally, T cells against auto-antigen are eliminated by apoptosis during the development. When the negative selection is deregulated (thymus diseases), T cells survive and abnormally proliferate, then attack self tissue, lead to autoimmune diseases.

  25. Mechanism of autoimmune diseases — Disrupted apoptosis of self-reactive cell Insertion mutation of Fas Point mutation of FasL Structural abnormity of FasL Decreased expression of Fas protein Escape the negative selection of self-reactive T cells Autoimmune diseases

  26. Rheumatoid arthritis • It is caused by decreased apoptosis and increased proliferation of arthral cell ; • Increased IL-1 and TGF-β1 and decreased Fas expression, which inhibit apoptosis; • Increased Bcl-2、Bcl-XL, which increased the threshold of apoptosis; • Resistance of T-cells to apoptosis.

  27. Excessive Apoptosis in Diseases AIDS, neurodegenerative diseases, aberrant myocardial ischemic-reperfusion

  28. （1）Acquired Immune Deficiency Syndrome —AIDS HIV infection increased Fas gene expression gp120glycoprotein expression + receptor in CD4 lymphocyte infusion of infected CD4 cell leads to syncytin formation produce tat protein (enhance Fas expression) secret TNF CD+4T- lymphocyte apoptosis AIDS

  29. (2) Cardiovascular diseases Cell death induced by ischemia-reperfusion Apoptosis Necrosis Early stage Later stage Peripheral region of infarct Center of infarct Mild ischemia Severe ischemia Chronic Acute

  30. Cardiovascular diseases (cont.) Possible mechanism (myocardial cell apoptosis induced by ischemia-reperfusion): (1) oxidative stress; (2) calcium overload; (3) p53 gene activation; (4) death receptor Fas, TNF over expressed.

  31. Cardiovascular diseases (cont.) Heart failure: Myocardial cell diminishes in pressure- overload-induced heart failure Possible mechanisms: Oxidative stress; cytokines; ischemia; hypoxia; pressure or volume overload, neural-endocrine system deregulation; Lead to myocardial cell apoptosis

  32. （3）Neurodegenerative diseases Alzheimer disease，Parkinson disease，Huntington disease，multiple sclerosis Factors involved in neuronal apoptosis: b-amyloid peptide, calcium overload, oxidative stress and neuronal growth factor insufficiency, etc. Lead to neuronal cell apoptosis

  33. Coexistence of Excessive and Insufficient Apoptosis in Diseases

  34. Coexistence of Excessive and Insufficient Apoptosis oxidative LDL platelet activation AgⅡ hypertension excess apoptosis insufficiency in in endothelium smooth muscle atherosclerosis

  35. Apoptosis and Diseases Diseases Mechanism Apoptosis Heart failure Ischemia, inflammation, etc. AIDS HIV infection of T4 cell AD, PD Ischemia, inflammation, etc Cancer P53, Bcl-2 Autoimune diseases Autoreactive T cells or B cells Atherosclerosis Endothelial cell, muscle cell

  36. Apoptosis Genes mutated in Diseases Gene Affected disease Tumor necrosis factor Familial periodic fever syndrome receptor 1 (TNF-R1) Fas (CD95; Apo-1) Autoimmune lymphoproliferative syndrome type I(ALPS I), malignant lymphoma, bladder cancer Fas ligand Systemic lupus erythematodes (only one case identified) Perforin Familial hemophagocytic lymphohistiocytosis (FHL) Caspase 10 Autoimmune lymphoproliferative syndrome type II (ALPS II) bcl-10 Non-Hodgkin’s lymphoma p53 Various malignant neoplasms Bax Colon cancer; hematopoetic malignancies bcl-2 Non-Hodgkin’s lymphoma c-IAP2 Low-grade MALT lymphoma NAIP1 Spinal muscular atrophy

  37. Principle of Treatment

  38. Thank you

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