non apopotic cell death, PAR polymer mediated cell death mechanism, PARP1 synthetase/transferase activity in cell death,

1. PARTHANATOS :
CELL DEATH MECHANISM

2. DEFINITION:-
 “Par” ; poly ADP-ribose.
“Thanatos” ; personification of death in Greek mythology.
 This is a PARP (Poly ADP-ribose Polymerase) mediated, well regulated cell death mechanism.
It’s proven that its different from APOPTOSIS because there is no Caspase activity as seen in
Apoptosis.

3. Mediators of Parthanatos &
it’s general conduct:-
 PARP 1 synthetase/ transferase
 PAR polymers
 AIF (apoptosis inducing factor)

4. Poly ADP-ribose Polymerase (PARP)
 Protein with 116kDa size, and is family of 17 proteins.
 It regulates homeostasis and genomic stability, among other possible or related functions
.PARP-1 is able to sense mild DNA damage in the form of single- strand nicks and breaks , and
through the synthesis of PAR polymer ,can facilitate the recruitment of the base excision repair
(BER) machinery.
 It has three major domains :
(i)an N-terminal domain(42kDa),which has two zinc-finger motifs and a nuclear location
sequence (NLS) for DNA binding;
(ii)a central auto modification domain (16kDa);
(iii)a C-terminal catalytic domain(55kDa) ,which features the nicotin

5. PARP activity :-
When there is DNA
damage detected by
PARP1, the PARP 1 is
activated which causes
formation of NAD+
PAR polymers are
synthesized in chained
fashion which encloses
PARP1. Tis process is
called are Parylation.
Also these Par proteins
bind to other DNA
binding proteins like
polymerases, ligases
and topoisomerases
IF HEAVY DAMAGE IS DETECTED THEN
HIGH POPULATION OF PAR LEADS TO
PARTHANATOS.
PARP formation can
be inhibited by PARP
inhibitors like
Benzamide.

6. MECHANISM OF CELL DEATH:-
PARP 1 detects extensive
damage.
PAR polymers are formed at
intensive rate.
These polymer stretch out
from nucleus to the
membrane and causes
externalization of
Phosphotidyl serine.
Later leading to
mitochondrial membrane
potential dissipation by
signalling proteins.
AIF (apoptosis inducing
factor) is released from the
outer membrane of
mitochondria which initiates
chromatinolysis and
chromosome shrinkage.

7. Triggers of Parthanatos :-
 Oxidative stress ; ROS, H2O2, hydroxyl radical formation
 Nitrosative stress ; NO, peroxynitrate (ONOO-)
 Inflammation, Ischaemia and DNA alkylating agents.
 This all causes Ca2+ influx but NMDA receptor activation plays important role in activation of
NO synthetase, leading to PARP1 activation.and cell death.
Injury causes release of
excitory
neurotransmitter,
glutamate, causes
excessive activation of it’s
ionotropic receptors.
(NMDA, AMPA)

8. Poly (ADP-ribose) glycohydrolase (PARG):-
 It is a protein found in cytosol which is responsible for degradation of PAR polymers and hence
is PAR regulator.
 Its activity of degradation is exoglycosidic/endoglycosidic. It degrades PARPs to free ADP ribose
units.
 Its 110kDa, with NLS.
 PARG knockout is term for PARG inhibition.
 Another enzyme, ADP ribose-(arginine) protein hydrolase (ARH3), also displays PARG-like
activity, butit does not seem to have an appreciable role in cell death , not being protective
against death or PAR accumulation.

9. AIF (Apoptosis Inducing factor) :-
 This is the ultimate protein of the cell death mediation in Parthanatos.
 This is responsible for DNA fragmentation (~50bp) and chromatin lysis.
 It’s a 67kDa protein which is processed into 62kDa one which is catalytic.
 Surface of the protein is +vely charged which lets it bind to protein easily.3domains
n terminal FAD binding domain
central reduced nicotinamide adenine dinucleotide (NADH) binding site
c terminal domain is responsible for cell death/Parthanatos

10. Activity of AIF :-
 There is also seen the release of cytochrome c for caspase activation which isn’t a major event in
Parthanatic cell.
 AIF release is regarded as “no return point”, since after this the process of cell death cant be reverted.
 Some suggested pathways are shown below:-
AIF IS
RELEASED
IT RECRUITS NUCLEASES AND
PROTEASES TO CAUSE FRAGS.
CYCLOPHILIN A
+
AIF
PROAPOPTOTIC DNA
FRAGMENTATION
COMPLEX
AIF NUCLEUS
LOCALISATION AND AIF
DEPENDENT
CHROMATINOLYSIS.
(hypoxic and ischaemic
conditions)
cofactor

11. ENDONUCLEASE G + AIF THIS COMPLEX IS KNOWN TO
CAUSE DNA FRAGMENTATION
IN MAMMALS THE SAME
COMPLEX IS TERMED AS
PAAN
(PARTHANATOS AIF
ASSOCIATED NUCLEASE)
CPS6, WHA1 shows
similar activity
found in c.elegans

13. PARTHANATOS
SIMILARITIES &
DIFFERENCES
BETWEEN OTHER
NON-APOPTOTIC
CELL DEATH
MECHANISMS

14. *Parthanatos:
mitochondrial-linked
mechanisms and therapeutic
opportunities
Amos A Fatokun1, Valina L Dawson2,3,4,5 and Ted M Dawson2,3,4
1Institute of Cell Signalling, School of Biomedical Sciences, University of Nottingham,
Nottingham, UK, 2Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,
Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3Department of Neurology,
Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4Department of Neuroscience,
Johns Hopkins University School of Medicine, Baltimore, MD, USA, and 5Department of
Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
*JAMES ANDREW RADOSEVICH ; APOPTOSIS AND BEYOND