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Overview of the main causes of nerve cell damage in CNS relating to a range of neurological conditions October 2013 Causes of Neuronal Damage and Degeneration in the CNS A number of different mechanisms are involved in neuronal cell damage and degeneration These include: • Apoptosis • Generation of inclusion bodies • Oxidative stress • Exocitotoxicity Combating neurodegenerative conditions involves defining which of these is the primary insult, what additional mechanisms are involved and why degenerative changes are progressive Targets for primary damage may be nerve cell body, axons, myelin, glial cells or - nutrient supply-blood vessels, blood brain barrier. Apoptosis • Apoptosis - usually referred to as “programmed cell death” • Neurones are generally thought to be irreplaceable-so not thought to be a normal programme of cell death in adults • May involve genetic damage affecting neuronal DNA • May involve loss of “trophic “ cell support-survival factors-e.g. hormonal, physiological or physical contact with other cells • May result from other insults that make the cell unviable Cell damage vs Cell protection and repair • Survival depends on the balance between survival factors and cell damage factors. • Treatment requires promotion of protection by supporting survival factors, inhibition of factors causing cell damage and promotion of repair but…… key information needed to define these is often missing or incomplete Also…..many biochemical and immunological systems change function in the presence of various confounding factors Apoptosis Pathways Death Receptors pathway. Membrane TNF forms trimers (TRAIL*) with fas ligands. Activates caspase 8 to form caspase 3 Two pathways Mitochondrial pathway. DNA damage activates p53 and pro-apoptotic proteins. Releases cytochrome c from mitochondria to drive apoptosis. Nitric oxide can be pro- or anti- apoptotic. TRAIL =tumor necrosis factor-a-related apoptosis-inducing ligand Apoptosis pathways Apoptosis Related Cell Death Cell death can be natural e.g. in development or abnormal e.g. in many neurological conditions Excessive apoptosis – feature of AD,PD and MS Also in CNS injury, O2 deprivation, infection. ??? Primary or secondary factor Cell death is mainly due to protease and lipase activity Defective apoptosis e.g. cancer, immune/autoimmune diseases such as myasthenia gravis, rheumatoid disease, asthma etc. Generation of Inclusion Bodies • Evident in neurones in PD, AD and Huntington’s disease. • Often associated with genetic characteristics that may or may not be inheritable • Key feature of inclusion bodies: – – – – – is failure to produce the “normal” structural version of proteins Insoluble Intercellular or extracellular Damaging to nerve cells Cells fail to extrude abnormal proteins Inclusion bodies • Characterised by misfolding of proteins normally expressed in neurones • Misfolding results in loss of important binding and amino acid reaction sites • Usually includes exposure of hydrophobic sites causing failure to form integrated protein structures • Aggregation of oligomers produces insoluble aggregates that damage the cell Generation of inclusion bodies Examples of Cellular Inclusions B. Tau Protein in Alzheimer's Disease C. a-Synuclein in Parkinson’s Disease Suggested Mechanism for cell to cell transfer of Lewy Bodies Types of inclusion bodies Disease Protein aggregate Pathology Prion Disease CJD,BSE Prion protein Extracellular amyloid plaques. Intracellular and axonal deposits Huntington’s Disease Mutant Huntingtin Neuronal inclusions, cytoplasmic aggregates and fibrillar fragments Parkinson’s Disease a-synuclein Intracellular Lewy Bodies fibrillar a-synuclein Alzheimer’s Disease Ab- or tau Extracellular neuritic plaques, intracellular fibrillary tangles of hyperphosphorylated tau Amyotrophic lateral sclerosis *SOD-1 *Superoxide Dismutase Intraneuronal inclusions insoluble SOD AD - Neurofibrillary Tangles and arrow shaped deposits Generation of tau derived inclusions in AD Stop Press! BBC News 10/09/2013 The discovery of the first chemical to prevent the death of brain tissue in a neuro -degenerative disease has been hailed as an exciting and historic moment in medical research. Nature October 2013 and Nature 485, 507–511 (24 May 2012) • • • Prof Mallucci, Kings: “What's really exciting is a compound has completely prevented neurodegeneration and that's a first” And: "What it gives you is an appealing concept that one pathway and therefore one treatment could have benefits across a range of disorders Prof Andy Randall, University of Bristol, said: "This is a fascinating piece of work. It will be interesting to see if similar processes occur in some of the common diseases with such deposits, for example Alzheimer's and Parkinson's disease. Potential Protein manufacture control route • eIF2a is a translation factor regulated in the presence of the unfolded protein response • UPR activation/increased elF2a seen in Az, PD and prion disease • Phosphorylated form of elF2a represses translation and leads to improved clinical status (shown experimentally by upregulated the expression of GADD34 activity) Short Break!! Oxidative Stress Reactive Oxygen Species -ROS • Production of oxygen free radicals as a result of mitochondrial oxidation and ATP production. H2O+ O2=H202 +oxygen free radical – Oxygen free radicals form reactive oxygen species (ROS) that attack membranes, DNA and enzyme systems in the cell. – “Normal” cellular reactions normally counteracted by Superoxide Dismutase (SOD) and anti-oxidants such as a tocopherol (Vit. E). – [NB SOD found in neurones in ALS in insoluble form associated with motoneurone death] Nitric Oxide- Reactive Nitric Species- NRS • Free Radical gas formed from oxygen and L-arginine in the presence of a catylising enzymes Nitric Oxide Synthase (NOS) enzymes are Inducable : iNOS (or NOS-11) Constitutive: eNOS (or NOS111) in endothelium nNOS (or NOS-1) in neurones Also in other tissues often having high cellular generation potential-e.g. myoblasts, osteoblasts NRS NO has important functions across a wide range of normal and pathological conditions. In Neurodenerative disease these include: • iNOS induced in macrophages in the presence of g-interferon with possible impact in immune mediated damage • Non adrenergic/non-cholinergic neurotransmitter in many tissues-e.g. gastric organs • Can be associated with cellular damage or protection-Action depends on cellular environment NO Regulation Endogenous and non-endogenous NO regulators • ADMA and DDAH endogenous NOS inhibitors – Inhibition of DDAH* by NO causes feedback inhibition of L arginine/NO pathway – Arginine analogues block production (L-NMMA and L-NAME) – – – – DDAH *dimethylarginine dimethylamonia hydrolase ADMA Asymetric Dimethylargenine L- NAME NG nitro-1-argenine-methyl-ester L-NMMA NG monomethyl-argenine Impact of NRS and ROS in the Brain Brain tissue is especially vulnerable to oxidative stress • Brain respiratory mechanisms are mostly Aerobic-little capacity for anaerobic metabolism • Hypoxia is easily induced –scarring, compromised blood flowimpact of systemic factors like BP • Promotes generation of superoxides Cellular features • Neurones and oligodendrocytes produce large surface area of proteolipid vulnerable to oxidative stress • NO also reduces axonal filament maintenance-leads to conduction abnormalities Excitotoxicity • Glutamate is a neurotransmitter but is highly toxic to neurones. • Glutamate activates *NMDA and **AMPA receptors • Action on NMDA Receptors allows Ca2+ to enter cell • Raised intracellular calcium will – Increase glutamate release – Activate proteases and lipases – Activate nitric oxide synthase. In presence of ROS generates hydroxyl Free radicals and peroxynitrite that damage DNA, membrane lipids and proteins NMDA Receptor Antagonist • • • • • N-methyl-D-aspartate receptor is normally activated by glutamate Excess glutamate can be detrimental and lead to cell death Memantine (Namenda) dampens glutamate effects via NMDA R Allows physiological NMDA R activities to continue Can be given with cholinesterase inhibitors Removal and metabolism of neurotransmitters Glutamate Clearance Spring 2011 MS Research Unit Glycine transporters at glycine synapses Other NT The heroes and Villains Immune overview Spring 2011 MS Research Unit In Summary • Cellular inclusions disorders include – Parkinson’s Disease – Amyolateral sclerosis (ALS) – Alzhiemer’s Disease – Huntington’s Disease May or may not have (inheritable)genetic component. Generally protein malformation is considered a primary pathology In Summary • A range of other conditions result from reactions affecting specific targets, or general reactions in response to ischemia, physical injury or other/metabolic trauma-e.g. Stroke, head Injury, poisoning. • Conditions having specific targets are: – PD: Dopamine producing cells of the Substantia Nigra – MS: Myelin in white mater of the brain and spine. Also grey matter/neurones/axons? – Motoneuron Disease: Brain and spinal neurones