Motor Neurone Disease Flashcards
What is happening in Motor Neurone
Disease?
- Loss of motor neurones in spinal cord, brainstem,
motor cortex. Muscle atrophy, loss of motor function, death. - Typical age of onset 50-60
- Average life expectancy 5 years from onset
- Incidence c. 1/100,000, 5-10% cases familial
- ca. 2000 people requiring care at any one time in UK
What is another name for Motor Neurone Disease?
Amyotrophic lateral sclerosis
Descending Corticospinal (Pyramidal) Motor Tracts?
Primary motor area of cerebral cortex is where the lateral and anterior corticospinal tract start and then run past the thalamus (via the internal capsule). They then pass through the medulla oblongata via the pyramid where lateral and anterior split and pass onto the cervical spinal cord where they then continue onto the lumbar spinal cord here the lateral corticospinal tract then connects with skeletal muscle.
Explain Motor neurone loss, the pathological changes in spinal cord, Bunina bodies and other inclusions
Check slide 7 for histological slides
What risk factors are associated with MND?
- Age
- Playing football professionally
- Smoking
- Lead exposure
- Military service
Causes of motor neurone cell death
- Non-genetic (environmental?) – 90% of cases. Cause unknown
- Familial ALS accounts for about 10% of all cases
– Mutations in SOD-1 (superoxide dismutase) 0.5% of sporadic ALS,
20% of FALS patients,
– Mutations in TDP43 – 1% sporadic cases, 1.5% familial cases.
– Mutations in fus – 1% sporadic cases, 5% familial cases,
– Repeat expansion in c9ORF72 – 7% sporadic cases, 25% of familial
cases.
Why do Motor Neurones die?
- Why do Motor Neurones degenerate selectively?
- Can we work out the processes and then create medicines to:
– Prevent them degenerating?
– Slow down their degeneration?
– Reverse their degeneration?
What is the pathogenic mechanism for MND?
- it’s not fully understood but these things could contribute:
- Viral infection
- Excess oxidation
- Excess Glutamate
- Abnormal structural proteins
- Ageing mitochondria
- Primary gene abnormalities
- Chronic vascular insufficiency
Explain the figure on slide 12
- There is impaired glutamate intake from the astrocyte causing excess glutamate to be present. This causes glutamate excitotoxicity as the pre-synatic neurones have more glutamate available to uptake.
- The astrocyte secretion toxic factors too
- Mutation of TARDBP, FUS, SOD1 genes result in TARDBP/ FUS production and a Mutant SOD1 which results in SOD1 aggregates.
- Ca2+ results in increased oxidative stress and mitochondrial dysfunction
- Neurofilament accumulation occurs
- There is dysfunction in the Na-K (sodium-potassium pump)
- Dysfunction of axonal transport systems
- Microglia release inflammatory mediators too
What is the link between glutamate and a failure of communication?
Glutamate dysregulation results in excitotoxicity
How do neurones “talk” to each other
via releasing chemical neurotransmitters
Explain excitotoxicity in motor neuron disease?
- Excessive stimulation of calcium-permeable glutamate receptors, due to:
- Excessive glutamate release
- Reduced clearance of glutamate (glutamate transported)
- Increased sensitivity of receptors
- Increased intracellular calcium
- Resulting in Excitotoxicity
Explain excitotoxicity in motor neuron disease (in terms of a diagram)
- Increase extracellular glutamate (due to release from the presynaptic neuronal terminal)
- This causes a decreased function and expression of glutamate transporters (as they can also be taken up by perisynaptic glial cells such as astrocytes)
- This increased expression of postsynaptic glutamate receptors such as NMDA and AMPA receptors (in the motor neurone) results in increased intracellular calcium (and sodium)
- This increase calcium and sodium causes neuronal death of the postsynaptic neurone as it also causes a decrease in ATP
Potential glutamate therapies in Motor Neurone Disease
- Reduce glutamate release (Riluzole)
- Block glutamate receptors
- Interfere in other ways with excitotoxic processes
- Improve glutamate uptake
What happens to glutamate transporters in mice with Motor neurone disease?
The glutamate transporters change in spinal cord
Describe modelleing transporter loss in simple systems
- Cultured Astrocytes
What do disease-causing SOD1 mutants do?
they down regulate transporters
Can increasing glutamate transport be neuroprotective?
Beta-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression
How are glutamate transporters lost? (explain via diagram)
- SOD1 proteins aggregate inside astrocytes, causing ER and mitochondria to activate the targeted proteolysis of EAAT2
- EAAT2 is usually used to prevent the conversion of Glu into iGluR
What are the effects of mutations of SOD1?
- The main role of SOD1 is to inactivate superoxide:
2H (+ hydrogen ions) +2O2 (- oxygen ions) -> 2Oc +2H2O
However this activity is present in mutant and wild-type SOD1. Transgenic mice lacking SOD1 do not develop ALS. Therefore loss of function doesnt causes ALS.
- SOD mutations may cause a gain of fuction.
e.g. Production of peroxynitrite. Peroxynitrite can cause inactivation of proteins (including glutamate transporter)
O2.- + NO -> ONOO- (peroxynitrite)
What are SOD1 mutants?
- Aggregation prone
– Causes proteostatic stress - Target mitochondria – aggregate in inner mitochondrial
membrane
– Causes loss of energy (ATP production)
– Oxidative stress?
– Calcium mobilisation – activation of cell death pathways?
TDP43 & fus
- Involved in RNA processing and movement of RNA in and
out of nucleus - Normally found in nucleus – in ALS found in aggregates
within cytoplasm - Is disease caused by a loss of normal function or a gain of
toxic function?
check slide 30
c9ORF72
- Repeat expansion in non-coding region of the gene
- Loss of normal function or gain of toxic function?
slide 31
Common pathological pathways in MND/ALS
- aggregates- slide 33
