Parthanatos (derived from the Greek Θάνατος, "Death") is a form of programmed cell death that is distinct from other cell death processes such as necrosis and apoptosis. While necrosis is caused by acute cell injury resulting in traumatic cell death and apoptosis is a highly controlled process signalled by apoptotic intracellular signals, parthanatos is caused by the accumulation of PAR and the nuclear translocation of apoptosis-inducing factor (AIF) from mitochondria. Parthanatos is also known as PARP-1 dependent cell death. PARP-1 mediates parthanatos when it is over-activated in response to extreme genomic stress and synthesizes PAR which causes nuclear translocation of AIF. Parthanatos is involved in diseases that afflict hundreds of millions of people worldwide. Well known diseases involving parthanatos include Parkinson's disease, stroke, heart attack, and diabetes. It also has potential use as a treatment for ameliorating disease and various medical conditions such as diabetes and obesity.
Parthanatos was first discovered in a 2006 paper by Yu et al. studying the increased production of mitochondrial reactive oxygen species (ROS) by hyperglycemia. This phenomenon is linked with negative effects arising from clinical complications of diabetes and obesity.
Researchers noticed that high glucose concentrations led to overproduction of reactive oxygen species and rapid fragmentation of mitochondria. Inhibition of mitochondrial pyruvate uptake blocked the increase of ROS, but did not prevent mitochondrial fragmentation. After incubating cells with the non-metabolizable stereoisomer L-glucose, neither reactive oxygen species increase nor mitochondrial fragmentation were observed. Ultimately, the researchers found that mitochondrial fragmentation mediated by the fission process is a necessary component for high glucose-induced respiration increase and ROS overproduction.
Extended exposure to high glucose conditions are similar to untreated diabetic conditions, and so the effects mirror each other. In this condition, the exposure creates a periodic and prolonged increase in ROS production along with mitochondrial morphology change. If mitochondrial fission was inhibited, the periodic fluctuation of ROS production in a high glucose environment was prevented. This research shows that when cell damage to the ROS is too great, PARP-1 will initiate cell death.
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that is found universally in all eukaryotes and is encoded by the PARP-1 gene. It belongs to the PARP family, which is a group of catalysts that transfer ADP-ribose units from NAD (nicotinamide dinucleotide) to protein targets, thus creating branched or linear polymers. The major domains of PARP-1 impart the ability to fulfill its functions. These protein sections include the DNA-binding domain on the N-terminus (allows PARP-1 to detect DNA breaks), the automodification domain (has a BRCA1 C terminus motif which is key for protein-protein interactions), and a catalytic site with the NAD+-fold (characteristic of mono-ADP ribosylating toxins).
Normally, PARP-1 is involved in a variety of functions that are important for cell homeostasis such as mitosis. Another of these roles is DNA repair, including the repair of base lesions and single-strand breaks. PARP-1 interacts with a wide variety of substrates including histones, DNA helicases, high mobility group proteins, topoisomerases I and II, single-strand break repair factors, base-excision repair factors, and several transcription factors.
PARP-1 accomplishes many of its roles through regulating poly(ADP-ribose) (PAR). PAR is a polymer that varies in length and can be either linear or branched. It is negatively charged which allows it to alter the function of the proteins it binds to either covalently or non-covalently. PAR binding affinity is strongest for branched polymers, weaker for long linear polymers and weakest for short linear polymers. PAR also binds selectively with differing strengths to the different histones. It is suspected that PARP-1 modulates processes (such as DNA repair, DNA transcription, and mitosis) through the binding of PAR to its target proteins.
The parthanatos pathway is activated by DNA damage caused by genotoxic stress or excitotoxicity. This damage is recognized by the PARP-1 enzyme which causes an upregulation in PAR. PAR causes translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus where it induces DNA fragmentation and ultimately cell death. This general pathway has been outlined now for almost a decade. While considerable success has been made in understanding the molecular events in parthanatos, efforts are still ongoing to completely identify all of the major players within the pathway, as well how spatial and temporal relationships between mediators affect them.
Extreme damage of DNA causing breaks and changes in chromatin structure have been shown to induce the parthanatos pathway. Stimuli that causes the DNA damage can come from a variety of different sources. Methylnitronitrosoguanidine, an alkylating agent, has been widely used in several studies to induce the parthanatos pathway. A noted number of other stimuli or toxic conditions have also been used to cause DNA damage such as H2O2, NO, and ONOO- generation (oxygenglucose deprivation).
The magnitude, length of exposure, type of cell used, and purity of the culture, are all factors that can influence the activation of the pathway. The damage must be extreme enough for the chromatin structure to be altered. This change in structure is recognized by the N-terminal zinc-finger domain on the PARP-1 protein. The protein can recognize both single and double DNA breaks.
Once the PARP-1 protein recognizes the DNA damage, it catalyzes post-transcriptional modification of PAR. PAR will be formed either as a branched or linear molecule. Branching and long-chain polymers will be more toxic to the cell than simple short polymers. The more extreme the DNA damage, the more PAR accumulates in the nucleus. Once enough PAR has accumulated, it will translocate from the nucleus into the cytosol. One study has suggested that PAR can translocate as a free polymer, however translocation of a protein-conjugated PAR cannot be ruled out and is in fact a topic of active research. PAR moves through the cytosol and enters the mitochondria through depolarization. Within the mitochondria, PAR binds directly to the AIF which has a PAR polymer binding site, causing the AIF to dissociate from the mitochondria. AIF is then translocated to the nucleus where it induces chromatin condensation and large scale (50Kb) DNA fragmentation. How AIF induces these effects is still unknown. It is thought that an AIF associated nuclease (PAAN) that is currently unidentified may be present. Human AIF have a DNA binding site that would indicate that AIF binds directly to the DNA in the nucleus directly causing the changes. However, as mice AIF do not have this binding domain and are still able to undergo parthanatos, it is evident that there must be another mechanism involved.
PAR, which is responsible for the activation of AIF, is regulated in the cell by the enzyme poly(ADP-ribose) glycohydrolase (PARG). After PAR is synthesized by PAR-1, it is degraded through a process catalyzed by PARG. PARG has been found to protect against PAR-mediated cell death while its deletion has increased toxicity through the accumulation of PAR.
Before the discovery of the PAR and AIF pathway, it was thought that the overactivation of PARP-1 lead to over consumption of NAD+. As a result of NAD+ depletion, a decrease of ATP production would occur, and the resulting loss of energy would kill the cell. However it is now known that this loss of energy would not be enough to account for cell death. In cells lacking PARG, activation of PARP-1 leads to cell death in the presence of ample NAD+.
Parthanatos is defined as a unique cell death pathway from apoptosis for a few key reasons. Primarily, apoptosis is dependent on the caspase pathway activated by cytochrome c release, while the parthanatos pathway is able to act independently of caspase. Furthermore, unlike apoptosis, parthanatos causes large scale DNA fragmentation (apoptosis only produces small scale fragmentation) and does not form apoptotic bodies. While parthanatos does share similarities with necrosis, is also has several differences. Necrosis is not a regulated pathway and does not undergo any controlled nuclear fragmentation. While parthanatos does involve loss of cell membrane integrity like necrosis, it is not accompanied by cell swelling.
|Membrane Blebbing||No||Yes||Yes, late|
The PAR enzyme was originally connected to neural degradation pathways in 1993. Elevated levels of nitric oxide (NO) have been shown to cause neurotoxicity in samples of rat hippocampal neurons. A deeper look into the effects of NO on neurons showed that nitric oxides cause damage to DNA strands; the damage in turn elicits PAR enzyme activity that leads to further degradation and neuronal death. PAR- blockers halted the cell death mechanisms in the presence of elevated NO levels.
PARP activity has also been linked to the neurodegenerative properties of toxin induced Parkinsonism. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that has been linked to neurodegeneration and development of Parkinson Disease-like symptoms in patients since 1983. The MPTP toxin’s effects were discovered when four people were intravenously injecting the toxin that they produced inadvertently when trying to street-synthesise the merpyridine (MPPP) drug. The link between MPTP and PARP was found later when research showed that the MPTP effects on neurons were reduced in mutated cells lacking the PARP gene. The same research also showed highly increased PARP activation in dopamine producing cells in the presence of MPTP.
Parthanatos, as a cell death pathway, is being increasingly linked to several syndromes connected with specific tissue damage outside of the nervous system. This is highlighted in the mechanism of streptozotocin (STZ) induced diabetes. STZ is a chemical that is naturally produced by the human body. However, in high doses, STZ has been shown to produce diabetic symptoms by damaging pancreatic β cells, which are insulin-producing. The degradation of β cells by STZ was linked to PARP in 1980 when studies showed that a PAR synthesis inhibitor reduced STZ’s effects on insulin synthesis. Inhibition of PARP causes pancreatic tissue to sustain insulin synthesis levels, and reduce β cell degradation even with elevated STZ toxin levels.
The multi-step nature of the parthanatos pathway allows for chemical manipulation of its activation and inhibition for use in therapy. This rapidly developing field seems to be currently focused on the use of PARP blockers as treatments for chronically degenerative illnesses. This culminated in 3rd generation inhibitors such as midazoquinolinone and isoquinolindione currently going to clinical trials.
Algor mortis (Latin: algor—coldness; mortis—of death), the second stage of death, is the change in body temperature post mortem, until the ambient temperature is matched. This is generally a steady decline, although if the ambient temperature is above the body temperature (such as in a hot desert), the change in temperature will be positive, as the (relatively) cooler body acclimates to the warmer environment. External factors can have a significant influence.
The term was first used by Dowler in 1849. The first published measurements of the intervals of temperature after death were done by Dr John Davey in 1839.Dead on arrival
Dead on arrival (DOA), also dead in the field and brought in dead (BID), indicates that a patient was found to be already clinically dead upon the arrival of professional medical assistance, often in the form of first responders such as emergency medical technicians, paramedics, or police.
In some jurisdictions, first responders must consult verbally with a physician before officially pronouncing a patient deceased, but once cardiopulmonary resuscitation is initiated, it must be continued until a physician can pronounce the patient dead.Death hoax
A death hoax is a deliberate or confused report of someone's death that turns out to be incorrect and murder rumors. In some cases it might be because the person has intentionally faked death.Death messenger
Death messengers, in former times, were those who were dispatched to spread the news that an inhabitant of their city or village had died. They were to wear unadorned black and go door to door with the message, "You are asked to attend the funeral of the departed __________ at (time, date, and place)." This was all they were allowed to say, and were to move on to the next house immediately after uttering the announcement. This tradition persisted in some areas to as late as the mid-19th century.Death pose
Dinosaur and bird fossils are frequently found in a characteristic posture consisting of head thrown back, tail extended, and mouth wide open. The cause of this posture—sometimes called a "death pose"—has been a matter of scientific debate. Traditional explanations ranged from strong ligaments in the animal's neck desiccating and contracting to draw the body into the pose, to water currents randomly arranging the remains in the position.Faux and Padian suggested in 2007 that the live animal was suffering opisthotonus during its death throes, and that the pose is not the result of any post-mortem process at all. They also reject the idea of water as responsible for randomly arranging the bodies in a "death pose", as different parts of the body and the limbs can be in different directions, which they found unlikely to be the result of moving water. They also found that the claim that drying out of ligaments would make the position does not seem believable either.
Alicia Cutler and colleagues from Brigham Young University in Provo, Utah, think it is related to water. In 2012, paleontologists Achim G. Reisdorf and Michael Wuttke published a study regarding death poses. According to the conclusions of this study, the so-called "opisthotonic posture" is not the result of a cerebral illness creating muscle spasms, and also not of a rapid burial. Rather, peri-mortem submersion resulted in buoyancy that enabled the Ligamentum elasticum to pull the head and tail back.Death rattle
Terminal respiratory secretions (or simply terminal secretions), known colloquially as a death rattle, are sounds often produced by someone who is near death as a result of fluids such as saliva and bronchial secretions accumulating in the throat and upper chest. Those who are dying may lose their ability to swallow and may have increased production of bronchial secretions, resulting in such an accumulation. Usually, two or three days earlier, the symptoms of approaching death can be observed as saliva accumulates in the throat, making it very difficult to take even a spoonful of water. Related symptoms can include shortness of breath and rapid chest movement. While death rattle is a strong indication that someone is near death, it can also be produced by other problems that cause interference with the swallowing reflex, such as brain injuries.It is sometimes misinterpreted as the sound of the person choking to death, or alternatively, that they are gargling.Dignified death
Dignified death is a somewhat elusive concept often related to suicide. One factor that has been cited as a core component of dignified death is maintaining a sense of control. Another view is that a truly dignified death is an extension of a dignified life. There is some concern that assisted suicide does not guarantee a dignified death, since some patients may experience complications such as nausea and vomiting. There is some concern that age discrimination denies the elderly a dignified death.Fan death
Fan death is a well-known superstition in Korean culture, where it is thought that running an electric fan in a closed room with unopened or no windows will prove fatal. Despite no concrete evidence to support the concept, belief in fan death persists to this day in Korea, and also to a lesser extent in Japan.Lazarus sign
The Lazarus sign or Lazarus reflex is a reflex movement in brain-dead or brainstem failure patients, which causes them to briefly raise their arms and drop them crossed on their chests (in a position similar to some Egyptian mummies). The phenomenon is named after the Biblical figure Lazarus of Bethany, whom Jesus Christ raised from the dead in the Gospel of John.Maceration (bone)
Maceration is a bone preparation technique whereby a clean skeleton is obtained from a vertebrate carcass by leaving it to decompose inside a closed container at near-constant temperature. This may be done as part of a forensic investigation, as a recovered body is too badly decomposed for a meaningful autopsy, but with enough flesh or skin remaining as to obscure macroscopically visible evidence, such as cut-marks. In most cases, maceration is done on the carcass of an animal for educational purposes.Megadeath
Megadeath (or megacorpse) is one million human deaths, usually caused by a nuclear explosion. The term was used by scientists and thinkers who strategized likely outcomes of all-out nuclear warfare.Necronym
A necronym (from the Greek words νεκρός, nekros, "dead" and ὄνομα ónoma, "name") is a reference to, or name of, a person who has died. Many cultures have taboos and traditions associated with referring to such a person. These vary from the extreme of never again speaking the person's real name, often using some circumlocution instead, to the opposite extreme of commemorating it incessantly by naming other things or people after the deceased.
For instance, in some cultures it is common for a newborn child to receive the name (a necronym) of a relative who has recently died, while in others to reuse such a name would be considered extremely inappropriate or even forbidden. While this varies from culture to culture, the use of necronyms is quite common.Necrophobia
Necrophobia is a specific phobia which is the irrational fear of dead things (e.g., corpses) as well as things associated with death (e.g., coffins, tombstones, funerals, cemeteries). With all types of emotions, obsession with death becomes evident in both fascination and objectification. In a cultural sense, necrophobia may also be used to mean a fear of the dead by a cultural group, e.g., a belief that the spirits of the dead will return to haunt the living.Symptoms include: shortness of breath, rapid breathing, irregular heartbeat, sweating, dry mouth and shaking, feeling sick and uneasy, psychological instability, and an altogether feeling of dread and trepidation. The sufferer may feel this phobia all the time. The sufferer may also experience this sensation when something triggers the fear, like a close encounter with a dead animal or the funeral of a loved one or friend. The fear may have developed when a person witnessed a death, or was forced to attend a funeral as a child. Some people experience this after viewing frightening media.The fear can manifest itself as a serious condition. Treatment options include medication and therapy.The word necrophobia is derived from the Greek nekros (νεκρός) for "corpse" and the Greek phobos (φόβος) for "fear".Obituary
An obituary (obit for short) is a news article that reports the recent death of a person, typically along with an account of the person's life and information about the upcoming funeral. In large cities and larger newspapers, obituaries are written only for people considered significant. In local newspapers, an obituary may be published for any local resident upon death. A necrology is a register or list of records of the deaths of people related to a particular organization, group or field, which may only contain the sparsest details, or small obituaries. Historical necrologies can be important sources of information.
Two types of paid advertisements are related to obituaries. One, known as a death notice, omits most biographical details and may be a legally required public notice under some circumstances. The other type, a paid memorial advertisement, is usually written by family members or friends, perhaps with assistance from a funeral home. Both types of paid advertisements are usually run as classified advertisements.Pallor mortis
Pallor mortis (Latin: pallor "paleness", mortis "of death"), the first stage of death, is an after-death paleness that occurs in those with light/white skin.Post-mortem interval
Post-mortem interval (PMI) is the time that has elapsed since a person has died. If the time in question is not known, a number of medical/scientific techniques are used to determine it. This also can refer to the stage of decomposition of the body.Rigor mortis
Rigor mortis (Latin: rigor "stiffness", mortis "of death"), or postmortem rigidity, is the third stage of death. It is one of the recognizable signs of death, characterized by stiffening of the limbs of the corpse caused by chemical changes in the muscles postmortem. In humans, rigor mortis can occur as soon as four hours after death.Skeletonization
Skeletonization refers to the final stage of decomposition, during which the last vestiges of the soft tissues of a corpse or carcass have decayed or dried to the point that the skeleton is exposed. By the end of the skeletonization process, all soft tissue will have been eliminated, leaving only disarticulated bones. In a temperate climate, it usually requires three weeks to several years for a body to completely decompose into a skeleton, depending on factors such as temperature, humidity, presence of insects, and submergence in a substrate such as water. In tropical climates, skeletonization can occur in weeks, while in tundra areas, skeletonization may take years or may never occur, if subzero temperatures persist. Natural embalming processes in peat bogs or salt deserts can delay the process indefinitely, sometimes resulting in natural mummification.The rate of skeletonization and the present condition of a corpse or carcass can be used to determine the time of death.After skeletonization, if scavenging animals do not destroy or remove the bones, acids in many fertile soils take about 20 years to completely dissolve the skeleton of mid- to large-size mammals, such as humans, leaving no trace of the organism. In neutral-pH soil or sand, the skeleton can persist for hundreds of years before it finally disintegrates. Alternately, especially in very fine, dry, salty, anoxic, or mildly alkaline soils, bones may undergo fossilization, converting into minerals that may persist indefinitely.Valina L. Dawson
Valina L. Dawson (born August 5, 1961) is an American neuroscientist who is the director of the Programs in Neuroregeneration and Stem Cells at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. She has joint appointments in the Department of Neurology, Neuroscience and Physiology. She is a member of the Graduate Program in Cellular and Molecular Medicine and Biochemistry, Cellular and Molecular Biology.