The tao of neuroscience
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The tao of neuroscience

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Life and Death at the molecular level

Life and Death at the molecular level

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  • 1. THE TAO OF NEUROSCIENCEDo we have an inbuilt molecular death mechanism in our genes, especially in ourbrain cells?Death is the only absolute biological phenomenon. Out of 100 individuals, 100will die.If we look at the macroscopic level, two of the main organs of the body the heartand the brain seem to have inbuilt death mechanisms. In both organs the cells donot regenerate. The heart coronary arteries lack adequate collateral circulation,making us more vulnerable to heart attacks. The brain uses more than 25% of thebody oxygen, yet it lacks sufficient antioxidant mechanisms to counteractoxidation. Seems like the evolution failed us in these vital areas of life, unless they were leftintentionally “un-evolved”.It seems that for biological systems life and death are the two sides of a coin or thetwo faces of Janus.Freud intuited this and postulated a death instinct in 1920. (Beyond the PleasurePrinciple, 1920).
  • 2. INADEQUATE BRAIN ANTIOXIDANTSThe CNS uses 25% of the body oxygen, but it does not have a proportionallyincreased concentration of antioxidants to counter this load. As such, the brain issusceptible to high levels of oxidative stress.Additionally neurons also utilize endogenous neurochemical redox reactions, suchas dopamine oxidation (Fenton reaction) and glutamate excitotoxicity.Moreover, the brain, and neurons in particular, contain large amounts ofpolyunsaturated fatty acids (PUFA) in membranes that are particularly vulnerablesubstrates 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 LEVELAt the molecular level there is a programmed cell death called apoptosis.This programmed cell suicide is genetically regulated and ready to be activated bythe 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 receptorThe 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 interactionwith specific ligands such as Fas protein (Krammer, 2000).FAS GENE - TNFRSF6Death receptors belong to the tumor necrosis factor (TNFR) gene superfamily ofreceptors (Ashkenazi 2001) and is encoded on chromosome 10q24.1, officialyknown as TNFRSF6.FAS PROTEINFas is the cell suicide protein. Upon binding to the death receptor, Fas transduces asignal that makes the cell kill itself. Fas mutations confer autoimmunity and increasedlymphocyte populations in the periphery.
  • 5. Subsequent signalling is mediated by the cytoplasmic part of the death receptorwhich contains a sequence termed the death domain (DD).Molecules such as FADD or TRADD possess their own DDs by which they arerecruited to the DDs of the activated death receptor, thereby forming the so-calleddeath inducing signalling complex (DISC). DISC activates pro-caspase 8, turns itinto 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 factorfamily it helps destroy malignant cells.Fas is a bad guy if we talk neurodegenerative diseases. By causing neuronalapoptosis, it contributes to disorders like Parkinson’s, Alzheimer’s and possiblyschizophrenia.Did nature do this “on purpose” to us? We seem doomed one way or another.INTRINSIC PATHWAYIs Bcl-2 family “dysfunctional”?On the outer mitochondrial membrane there are two kinds of proteins. One groupfacilitates mitochondrial damage (such as BAX). The other group facilitatesmitochondrial 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 bypatching these pores.Bcl-2 gene family codes for both groups of pro-survival and pro-apoptoticproteins.
  • 6. Here too Bcl-2 protein prevents apoptosis. This is desirable in neurodegenerativedisorders, but undesirable in cancer. Did evolution fail us here or was this deathmechanism inbuilt into our system?P53 the master switch (good guy for oncologists, bad guy forneuropsychiatrists)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 cellcycle. 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) and2. triggering of apoptosis (Heinrichs & Deppert 2003).
  • 7. p53 is a nuclear transcription factor that binds to defined sites within the DNA. Itregulates these genes either by- transcriptional activation (Murphy et al. 1999) or by- modulating other protein activities by direct binding (Guimaraes & Hainaut2002).An interesting question is what determines the choice between growth arrest andapoptosis.Although the function of p53 as a tumor suppressor ensures that we cant livewithout it, it was recently discovered that p53 induces apoptosis and as such is apro-aging and pro-senescence factor.An article in the Journal ONCOGENE (2011,1-15) identifies p53 as an inhibitor ofpro-longevity FoxO3 gene.( V.M. Renault -The pro-longevity gene FoxO3 is a direct target of the p53tumor suppressor).Again standing in front of a two faced Janus. Seems like nature does no wasteideas since for it life and death are one and the same phenomenon.Adonis Sfera, MD