16Neuro - Motor Neuron Disease Flashcards
What are the features of motor neuron disease?
Late onset (typically between 50-65 years)
Progressive and ultimately fatal degeneration of motor neurons in BRAINSTEM, MOTOR CORTEX AND SPINAL CORD = also has effects on other areas of the brain
Symptoms include:
Weakness
Spasticity
Progressive paralysis
Death due to RESPIRATORY FAILURE = no cure
What is the incidence of motor neuron disease?
Incidence: 1-2/100 000; more common in men; incidence increases with age
What is the different nomenclature for motor neuron disease?
In the USA, MND refers to a spectrum of diseases including Amyotrophic Lateral Sclerosis
In the UK, MND = ALS
Who first described motor neuron disease?
Motor neuron disease was first described by Jean-Martin Charcot in 1869
What are the typical pathologies affecting those with motor neuron disease?
MND/ALS include a range of pathologies:
Oxidative damage, excitotoxicity = affecting neurons leading to disruption and cell death
Defects in axonal transport
Deficient protein quality control/protein aggregation
Changes in RNA processing
What is the link between motor neuron disease and dementia?
Not associated with dementia but 10-15% of MND patients develop Frontotemporal Lobar Dementia (FTLD)
Almost all MND and 50% of FTLD patients show TDP43 CONTAINING PROTEIN AGGREGATES
Within how many years of diagnosis does death usually occur?
Death typically occurs within 5 years of diagnosis
What is the epidemiology of sporadic Motor neurone disease?
90-95% of cases are SPORADIC = unknown cause Risk factors may include: Exercise! = oxidative stress associated with exercise Possibly free radical related: Smoking Pesticides/herbicides exposure Heavy metals exposure High glutamate diet - MSG High fat diet
What is the epidemiology of familial Motor neurone disease?
10% of cases are FAMILIAL
Hereditary form of ALS known as familial:
Familial Amyotrophic Lateral Sclerosis (FALS)
Type 1: Age-dependent AUTOSOMAL DOMINANT trait
10-20% of cases of FMND/FALS associated with mutations in SUPEROXIDE DISMUTASE (SOD1)
SOD part of the defense against free radicals
SOD1 is found in the cytosol
Genetic risk factors
Various polymorphisms associated with INCREASED RISK of MND e.g. TDP43
SOD1 and TDP-43 are the most important mutated genes clinically (not much is known about C9orf72)
What is the link between motor neuron disease and SOD1?
SOD1 converts superoxide into hydrogen peroxide = is found in cytosol
Superoxide = some of it comes from the mitochondria = monoradicals can combine with other radicals to become more harmful
Mutations in superoxide dismutase (SOD1), an enzyme involved in free radical defense found in families with FMND/FALS
20% of FMND, 2% of total MND
Also a genetic risk factor
Mutations throughout polypeptide
A4V (alanine to valine mutation at codon 4) in 50% of cases, most aggressive
Mutations may reduce function (toxic loss of function) or alter (toxic gain of function) superoxide dismutase activity
Different mutations with different geographical distributions
What is the action of SOD1?
SOD1 is a Cu2+ and Zn2+ containing enzyme which removes the superoxide radical
TOXIC GAIN OF FUNCTION probable with FMND/FALS SOD1 mutants
Some SOD1 mutants have more open channel to Cu2+
Entry of H2O2 to Cu2+ to form •OH = more damaging
Looser binding of Cu2+ in Fenton reaction produces •OH radical
Nitronium ion = nitrosylates tyrosine = may prevent tyr phosphorylation = disrupts signalling pathways
Mutant SOD1 more prone to aggregation
What is the interaction between SOD1 and Rac1?
Wild-type SOD1 interacts with Rac1 (a signalling G protein) a regulator of NADPH oxidase in neurons (Nox1) and microglia (Nox2)
Mutant SOD1 increases affinity for Rac1 which locks Nox in active superoxide producing form
May be a trigger for the disease
Nox inhibitors improve survival in SOD1 mutant mice
Describe the interactions between mSOD1 and the ubiquitin-proteasome system.
mSOD1 aggregates inhibit the proteasome system = aggregates build up in the proteasome
mSOD1 interacts with Derlin 1 (Degradation in Endoplasmic Reticulum Protein 1), a component of the ERAD pathway
Derlin 1 involved in reverse translocation and degradation of ER proteins
mSOD1 mutants inhibit ERAD, therefore accumulation of misfolded proteins
Misfolded protein accumulation activates ASK1 (Apoptosis Signal-Regulating Kinase 1), a kinase involved in apoptosis
What is the link between SOD1 and the mitochondria?
mSOD1 associates with outer mitochondrial membrane in neurons
Release of cytochrome C = a pro-apoptotic signal
Leakage of electrons leads to formation of free radicals
mSOD1 causes oxidative stress in astrocyte mitochondria
Damage to neighbouring neurons
mSOD1 impairs mitochondrial calcium buffering = normally mitochondria can sequester calcium ions from the cytosol = this stops leading to higher cytosolic calcium concentrations
What other genetic factors have been linked to SOD1?
TDP43 and FUS relocate in cytosol in FMND and SMND = causing aggregation
Relocalised FUS and TDP43 is associated with the appearance of misfolded/aggregated SOD1
Aggregated (wt)SOD1 appears to propagate in a prion-like fashion
Why are motor neurons particularly affected in this disease?
If SOD1 activity in FMND/FALS altered in all cell types why are motor neurons damaged?
High levels of SOD1 in motor neurons
Long axonal processes in motor neurons, more neurofilaments
High metabolic load in motor neurons, more ETC activity = more free radicals = more leakage of electrons from the ETC
Low Ca2+ buffering capacity = calcium concentration changes are more pronounced
Glutamate excitotoxicity and effects of free radical damage on calcium homeostasis
Glutamate hypothesis = glutamate is a neurotransmitter
How does glutamate cause excitotoxicity in the cell?
Glutamate acts as an extracellular signal (neurotransmitter) Glutamate receptors (GluR) present on cell surface of motor neurons When GluR occupied by Glutamate Ca2+ channel opens and Ca2+ enters the cell from the extracellular space NMDA (N-methyl D-aspartate) receptor (a form of GluR) produces a slow and prolonged calcium response AMPA GluR produce a fast and short calcium response Regulate various processes Also activate processes than can lead to cell death = change in Ca2+ concentration
What happens following glutamate stimulation of glutamate receptors on motor neurons?
Glutamate acts as an extracellular signal (neurotransmitter) Glutamate receptors (GluR) present on cell surface of motor neurons When GluR occupied by Glutamate Ca2+ channel opens and Ca2+ enters the cell from the extracellular space NMDA (N-methyl D-aspartate) receptor (a form of GluR) produces a slow and prolonged calcium response AMPA GluR produce a fast and short calcium response Regulate various processes Also activate processes than can lead to cell death = change in Ca2+ concentration
What effect does prolonged high intracellular calcium have on a cell?
Prolonged high intracellular calcium will activate a calcium dependent protease, calpain
Calpain proteolytically modifies Xanthine dehydrogenase to Xanthine oxidase which converts xanthine into urea, H2O2 and O2•-
Calcium activates nitric oxide synthase which generates NO•
NO• reacts with H2O2 to produce hydroxyl radical, HO• or with O2•- to produce peroxynitrite
Why is excitotoxicity a particular problem for cells with impaired ATP production?
This is always a potential threat but becomes a particular danger where ATP production is impaired and Ca(II) buffering capacity is impaired
Why is excitotoxicity important in motor neuron disease?
Motor neurons have low levels of receptor GluR subunits (AMPA GluRs) resulting in increased Ca2+ influx in motor neurons
Free radical damage to glutamate re-uptake system of astrocytes (EAAT2) leads to elevated extracellular glutamate and therefore elevated intracellular Ca2+
Death of MNs releases more glutamate to extracellular space
MNs low in calcium buffering proteins even in healthy cells
How does mSOD1 and excitotoxicity link together?
Mutant SOD1 can lead to mitochondrial damage resulting in MND but downstream of primary cause
GluRs/excitotoxicity may “sensitise” motor neurons to primary insult
What were the results of experiments carried out on transgenic mice?
Mice with normal human SOD or mutant SOD with increased activity, developed MND symptoms rapidly (increased SOD activity)
Mice expressing mutant human SOD, with decreased SOD activity, develop MND, but more slowly
G39A, G37R mutations lead to vacuolation, inclusions (SOD1, ubiquitin and neurofilaments)
Nitrotyrosine detected in neurofilaments, also increased protein carbonyls and lipid peroxidation
Vitamin E and Riluzole (GluR antagonist) slow progression
What role does mSOD1 play in aggregation?
Mutant SOD may interact with neurofilament proteins and release Zn2+ = transition metal = Fenton reaction = hydroxide radicals
Site-specific free radical damage leads to NF aggregates
Disrupt cell architecture and axonal transport
Mutant SOD more prone to aggregation
