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Transcript
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