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APOPTOSIS. What is it? Why is it important? How is it controlled? What is its role in age-related disease?. APOPTOSIS. Programmed cell death Orderly cellular self destruction Process: as crucial for survival of multi-cellular organisms as cell division MULTIPLE FORMS???.

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slide1

APOPTOSIS

What is it?

Why is it important?

How is it controlled?

What is its role in age-related disease?

slide2

APOPTOSIS

Programmed cell death

Orderly cellular self destruction

Process: as crucial for survival of multi-cellular

organisms as cell division

MULTIPLE FORMS???

slide3

Forms of cell death

"Classic"

Necrosis Apoptosis Mitotic catastrophe

Passive Active Passive

Pathological Physiological or Pathological

pathological

Swelling, lysis Condensation, Swelling, lysis

cross-linking

Dissipates Phagocytosed Dissipates

Inflammation No inflammation Inflammation

Externally induced Internally or Internally induced

externally induced

slide4

APOPTOSIS

  • Evolutionarily conserved
  • Occurs in all multicellular animals studies (plants too!)
  • Stages and genes conserved from nematodes (worms)
  • and flies to mice and humans
slide5

STAGES OF CLASSIC APOPTOSIS

Healthy cell

DEATH SIGNAL (extrinsic or intrinsic)

Commitment to die (reversible)

EXECUTION (irreversible)

Dead cell (condensed, crosslinked)

ENGULFMENT (macrophages, neighboring cells)

DEGRADATION

slide6

STAGES OF CLASSIC APOPTOSIS

Genetically controlled: Caenorhabditis elegans

soil nematode (worm)

ces2

ced9

ces1

ced3,4

Dead cell

Healthy cell

Committed cell

BCL2

Caspases

(proteases)

C. elegans genes == mammalian genes

slide7

Cells are balanced between life and death

DAMAGE

Physiological death signals

DEATH SIGNAL

ANTIAPOPTOTIC

PROTEINS

(dozens!)

PROAPOPTOTIC

PROTEINS

(dozens!)

DEATH

slide8

APOPTOSIS: important in embryogenesis

Morphogenesis (eliminates excess cells):

Selection (eliminates non-functional cells):

slide9

APOPTOSIS: important in embryogenesis

Immunity (eliminates dangerous cells):

Self antigen

recognizing cell

Organ size (eliminates excess cells):

slide10

APOPTOSIS: important in adults

Tissue remodeling (eliminates cells no longer needed):

Apoptosis

Involution

(non-pregnant, non-lactating)

Late pregnancy, lactation

Virgin mammary gland

- Testosterone

Apoptosis

Prostate gland

slide11

APOPTOSIS: important in adults

Tissue remodeling (eliminates cells no longer needed):

Apoptosis

+ antigen (e.g. infection)

- antigen (e.g. recovery)

Resting lymphocytes

Steroid immunosuppressants: kill

lymphocytes by apoptosis

Lymphocytes poised to die by apoptosis

slide12

X

APOPTOSIS: important in adults

Maintains organ size and function:

Apoptosis

+ cell division

Cells lost by apoptosis are replaced by cell division

(remember limited replicative potential of normal cells

restricts how many times this can occur before

tissue renewal declines)

slide13

APOPTOSIS: control

Receptor pathway (physiological):

FAS ligand

TNF

Death receptors:

(FAS, TNF-R, etc)

Death

domains

Adaptor proteins

Pro-caspase 8 (inactive)

Caspase 8 (active)

Pro-execution caspase (inactive)

Execution caspase (active)

MITOCHONDRIA

Death

slide14

APOPTOSIS: control

Intrinsic pathway (damage):

Mitochondria

Cytochrome c release

BAX

BAK

BOK

BCL-Xs

BAD

BID

B IK

BIM

NIP3

BNIP3

BCL-2

BCL-XL

BCL-W

MCL1

BFL1

DIVA

NR-13

Several

viral

proteins

Pro-caspase 9 cleavage

Pro-execution caspase (3) cleavage

Caspase (3) cleavage of cellular proteins,

nuclease activation,

etc.

Death

slide15

APOPTOSIS: control

Physiological Intrinsic

receptor pathway damage pathway

MITOCHONDRIAL SIGNALS

Caspase cleavage cascade

Orderly cleavage of proteins and DNA

CROSSLINKING OF CELL CORPSES; ENGULFMENT

(no inflammation)

slide16

APOPTOSIS: Role in Disease

TOO MUCH: Tissue atrophy

Neurodegeneration

Thin skin

etc

TOO LITTLE: Hyperplasia

Cancer

Athersclerosis

etc

slide17

APOPTOSIS: Role in Disease

Neurodegeneration

Neurons are post-mitotic (cannot replace themselves;

neuronal stem cell replacement is inefficient)

Neuronal death caused by loss of proper connections,

loss of proper growth factors (e.g. NGF), and/or

damage (especially oxidative damage)

Neuronal dysfunction or damage results in loss of synapses

or loss of cell bodies

(synaptosis, can be reversible; apopsosis, irreversible)

PARKINSON'S DISEASE

ALZHEIMER'S DISEASE

HUNTINGTON'S DISEASE etc.

slide18

APOPTOSIS: Role in Disease

Cancer

Apoptosis eliminates damaged cells

(damage => mutations => cancer

Tumor suppressor p53 controls senescence

and apoptosis responses to damage

Most cancer cells are defective in apoptotic response

(damaged, mutant cells survive)

High levels of anti-apoptotic proteins

or

Low levels of pro-apoptotic proteins

===> CANCER

slide19

APOPTOSIS: Role in Disease

AGING

Aging --> both too much and too little apoptosis

(evidence for both)

Too much (accumulated oxidative damage?)

---> tissue degeneration

Too little (defective sensors, signals?

---> dysfunctional cells accumulate

hyperplasia (precancerous lesions)

slide20

OPTIMAL FUNCTION (HEALTH)

APOPTOSIS

AGING

APOPTOSIS

Neurodegeneration, cancer, …..