The document discusses molecular mechanisms of cell death in the brain and questions whether they represent a failure of evolution or were intentionally designed. It describes two main pathways for programmed cell death (apoptosis) - the intrinsic pathway involving mitochondria and the extrinsic pathway mediated by death receptors like Fas. Key proteins involved in these pathways like Bcl-2, Bax, and p53 are discussed in the context of regulating cell survival versus death. The document poses the question of whether nature intended for these death mechanisms or if evolution failed to prevent vulnerability in the brain.

1. THE TAO OF NEUROSCIENCE
Do we have an inbuilt molecular death mechanism in our genes, especially in our
brain cells?
Death is the only absolute biological phenomenon. Out of 100 individuals, 100
will die.
If we look at the macroscopic level, two of the main organs of the body the heart
and the brain seem to have inbuilt death mechanisms. In both organs the cells do
not regenerate. The heart coronary arteries lack adequate collateral circulation,
making us more vulnerable to heart attacks. The brain uses more than 25% of the
body oxygen, yet it lacks sufficient antioxidant mechanisms to counteract
oxidation.
Seems like the evolution failed us in these vital areas of life, unless they were left
intentionally “un-evolved”.
It seems that for biological systems life and death are the two sides of a coin or the
two faces of Janus.
Freud intuited this and postulated a death instinct in 1920. (Beyond the Pleasure
Principle, 1920).

2. INADEQUATE BRAIN ANTIOXIDANTS
The CNS uses 25% of the body oxygen, but it does not have a proportionally
increased concentration of antioxidants to counter this load. As such, the brain is
susceptible to high levels of oxidative stress.
Additionally neurons also utilize endogenous neurochemical redox reactions, such
as dopamine oxidation (Fenton reaction) and glutamate excitotoxicity.
Moreover, the brain, and neurons in particular, contain large amounts of
polyunsaturated fatty acids (PUFA) in membranes that are particularly vulnerable
substrates of oxidation.(Brain Protection in Schizophrenia and Mood Disorders,
Michael S.Ritsner, 2010).
Is this vulnerability “the intention” of nature or a failure of evolution?

3. DEATH AT THE MOLECULAR LEVEL
At the molecular level there is a programmed cell death called apoptosis.
This programmed cell suicide is genetically regulated and ready to be activated by
the death inducing stimuli (Ishizaki, 1995; Weil, 1996).
Apoptosis occurs by one of the two pathways: intrinsic and extrinsic.
The extrinsic pathway involves a death-ligand and death receptor
The intrinsic pathway involves the mitochondrion.
EXTRINSIC PATHWAY

4. Extrinsic apoptosis is mediated by the activation of so called “death receptors”
which are cell surface receptors that transmit apoptotic signals after interaction
with specific ligands such as Fas protein (Krammer, 2000).
FAS GENE - TNFRSF6
Death receptors belong to the tumor necrosis factor (TNFR) gene superfamily of
receptors (Ashkenazi 2001) and is encoded on chromosome 10q24.1, officialy
known as TNFRSF6.
FAS PROTEIN
Fas is the cell suicide protein. Upon binding to the death receptor, Fas transduces a
signal that makes the cell kill itself. Fas mutations confer autoimmunity and increased
lymphocyte populations in the periphery.

5. Subsequent signalling is mediated by the cytoplasmic part of the death receptor
which contains a sequence termed the death domain (DD).
Molecules such as FADD or TRADD possess their own DDs by which they are
recruited to the DDs of the activated death receptor, thereby forming the so-called
death inducing signalling complex (DISC). DISC activates pro-caspase 8, turns it
into caspase 8 which cleaves specific substrates resulting in cell death (Scaffidi,
1998).
So, is Fas a pro-life or pro-death protein? The answer is yes.
Fas is a good guy if we talk about cancer. As part of the tumor necrosing factor
family it helps destroy malignant cells.
Fas is a bad guy if we talk neurodegenerative diseases. By causing neuronal
apoptosis, it contributes to disorders like Parkinson’s, Alzheimer’s and possibly
schizophrenia.
Did nature do this “on purpose” to us? We seem doomed one way or another.
INTRINSIC PATHWAY
Is Bcl-2 family “dysfunctional”?
On the outer mitochondrial membrane there are two kinds of proteins. One group
facilitates mitochondrial damage (such as BAX). The other group facilitates
mitochondrial repair (such as Bcl-2).
Bax protein damages the mitochondrion by perforating the outer membrane,
forming pores. Bcl-2 protein protects the mitochondrial outer membrane by
patching these pores.
Bcl-2 gene family codes for both groups of pro-survival and pro-apoptotic
proteins.

6. Here too Bcl-2 protein prevents apoptosis. This is desirable in neurodegenerative
disorders, but undesirable in cancer. Did evolution fail us here or was this death
mechanism inbuilt into our system?
P53 the master switch (good guy for oncologists, bad guy for
neuropsychiatrists)
Another cool protein is p52 – It was called “the guardian of the genom”.
P 53(protein 53) is a tumor suppressor protein. It is essential in regulating the cell
cycle. In most human cancers, p 53 functions incorrectly. (Vogelstein et al. 2000).
Of the many functions of p53, two are crucial:
1. inhibition of abnormal growth of cells (reviewed by Sionov & Haupt 1999) and
2. triggering of apoptosis (Heinrichs & Deppert 2003).

7. p53 is a nuclear transcription factor that binds to defined sites within the DNA. It
regulates these genes either by
- transcriptional activation (Murphy et al. 1999) or by
- modulating other protein activities by direct binding (Guimaraes & Hainaut
2002).
An interesting question is what determines the choice between growth arrest and
apoptosis.
Although the function of p53 as a tumor suppressor ensures that we can't live
without it, it was recently discovered that p53 induces apoptosis and as such is a
pro-aging and pro-senescence factor.
An article in the Journal ONCOGENE (2011,1-15) identifies p53 as an inhibitor of
pro-longevity FoxO3 gene.( V.M. Renault -The pro-longevity gene FoxO3 is a direct target of the p53
tumor suppressor).
Again standing in front of a two faced Janus. Seems like nature does no waste
ideas since for it life and death are one and the same phenomenon.
Adonis Sfera, MD