Apoptosis and DiseasesApoptosis and Diseases

1. Concept 2. Major pathways 3. Key molecules4. Apoptosis-related diseases

• Insufficient apoptosis in diseases• Excessive apoptosis in diseases• Coexistence of insufficient and excessive

apoptosis in diseases5. Principles of treatment

ContentsContents

History of Cell Death ResearchHistory of Cell Death Research

Using C. elegan as a model

A highly regulated active cell death

characterized by cell shrinkage and

nuclear condensation.

pre-programed, cascade events ATP, gene expression

Morphology opposite to necrosis

Apoptosis or Programmed Cell DeathApoptosis or Programmed Cell Death

What is the difference of programmed cell death and apoptosis?

Apoptosis Necrosis

Nature Physiological or pathological; specific

Pathological, accidental

Stimulus Mild Strong

Biochemistry Active, energy-dependent, new protein synthesis

Passive, energy-independent, no protein synthesis

DNA

Morphology

Specific degradation, ladder (180-200 bp)

Intact, shrinkage, condensation

Random degradation

Lysis, swelling

Inflammation No Yes

Apoptotic body Yes No

Gene regulation Yes No

Apoptosis and NecrosisApoptosis and Necrosis

Initiation

Regulation

Execution

Phagocytosis

Physiological, e.g., growth factors, estrogen; virus; chemicals.

Inhibitory FactorsStimulatory FactorsPhysiological, FasL;Pathological, glutamate, free radicals;therapeutical, herb.

Conserved

Apoptotic ProcessApoptotic Process

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

• Death receptor-mediated apoptotic pathway

• Mitochondria-mediated apoptotic pathway

• Nuclear-mediated apoptotic pathway

Apoptotic PathwaysApoptotic Pathways

death-inducing signaling complex

Fas-associating protein withdeath domain

Apoptotic PathwaysApoptotic Pathways

Mitochondrial Membrane Permeabilization (MMP) in Apoptotic Process

Mitochondrial Membrane Permeabilization (MMP) in Apoptotic Process

ER and ApoptosisER and Apoptosis

Cross-talking among Organelles and Molecules in Apoptosis

1. Activation of endonuclease

2. Activation of caspases

DNA ladder

Collapse of cell and nucleus

Executors Executors

Role of Endonuclease180-200 bp

H1ZnZn2+

CaCa2+ MgMg2+

Endonuclease

Role of Caspases

(Focal adhesion kinase)

(p21-activated kinase 2)

(Ste20-related kinase)

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

2. Bcl-2 family ： anti-apoptotic: Bcl-2 (B cell lymphoma/leukemia), Bcl-XL

pro-apoptotic: Bax, Bad

Key MoleculesKey Molecules

1. Caspases: Caspase-3,Caspase-8,Caspase-9, etc.

3. Others: Apaf-1(apoptosis activating factor-1), cytochrome C, IAPs, p53, etc.

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.

Apoptosis-related DiseasesApoptosis-related Diseases

Growth Apoptosis

Balance of Growth and ApoptosisBalance of Growth and Apoptosis

Autoimmune disease,Tumor, virus infection, etc

Proliferation

Apoptosis

Insufficient Apoptosis in DiseasesInsufficient Apoptosis in Diseases

(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

(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.

Mechanism of autoimmune diseases — Disrupted apoptosis of self-reactive cell

Point mutation of FasL

Insertion mutation of Fas

Structural abnormity of FasL

Decreased expression of Fas protein

Escape the negative selection of self-reactive

T cells

Autoimmune diseases

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.

AIDS, neurodegenerative diseases, aberrant

myocardial ischemic-reperfusion

Excessive Apoptosis in DiseasesExcessive Apoptosis in Diseases

（ 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

(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

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.

Cardiovascular diseases (cont.)

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

Alzheimer disease ， Parkinson disease ， Huntington disease ， multiple

sclerosis

Factors involved in neuronal apoptosis:

amyloid peptide, calcium overload,

oxidative stress and neuronal growth factor

insufficiency, etc.

Lead to neuronal cell apoptosis

（ 3 ） Neurodegenerative diseases

Coexistence of Excessive and Insufficient Apoptosis in Diseases

Coexistence of Excessive and Insufficient Apoptosis in Diseases

oxidative LDL

platelet activation Ag Ⅱ

hypertension

excess apoptosis insufficiency in in endothelium smooth muscle

atherosclerosis

Coexistence of Excessive and Insufficient Apoptosis

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

Apoptosis and DiseasesApoptosis and Diseases

Gene Affected diseaseTumor necrosis factor Familial periodic fever syndrome receptor 1 (TNF-R1)Fas (CD95; Apo-1) Autoimmune lymphoproliferative syndrome type I(ALPS I), malignant lymphoma, bladder cancerFas 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 lymphomap53 Various malignant neoplasmsBax Colon cancer; hematopoetic malignanciesbcl-2 Non-Hodgkin’s lymphomac-IAP2 Low-grade MALT lymphomaNAIP1 Spinal muscular atrophy

Apoptosis Genes mutated in DiseasesApoptosis Genes mutated in Diseases

Principle of TreatmentPrinciple of Treatment

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