Lecture 22 - Motor Neurone Disease Flashcards Preview

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Flashcards in Lecture 22 - Motor Neurone Disease Deck (36):

Give a brief description of MND

A group of diseases
• The most common of which is Amyotrophic lateral scerlosis

• Affects motor neurons

• Progressive
• Fatal


What are the symptoms of MND?

1. Loss of muscle function:
• Muscle twitching
• Muscle weakness
• Difficulty speaking
• Difficulty swallowing
• Tripping, stumbling, dropping things
• Progressive paralysis
• Decreased respiratory function

2. Loss of muscle mass
• Muscle atrophy


What are the two forms of motor neurons?
Which are affected in MND?

Upper motor neurons
• Originate in brain / brain stem
• Do not directly innervate muscle

Lower motor neurons
• Directly innervate muscle
• Originate in the spinal cord

Both are affected in MND


What is the average age of onset of MND?

45-60 years

Mid-late adulthood, after reproduction


What happens to sensory neurons in MND?

Usually spared


What happens to cognitive ability in MND?

Generally thought to be spared
May be some degeneration (?)


How is MND diagnosed?

Why is this so?

Diagnosis is purely clinical (no test)
• Process of exclusion
• Not easy to diagnose
• Much uncertainty about diagnosis

Hard to diagnose because the underlying causes are not known


What is the prognosis of MND?

• Progressive: continues getting worse

• Timeframe for symptom progression is variable

• Confined to wheelchair within 1-2 years
• Death within 3-5 years


What normally causes death in MND?

Respiratory failure


What treatments are there at the moment for MND?

• Only drug on the market
• Moderate, controversial clinical efficacy
• Works by enhancing glutamate uptake from the synapse


What was seen in the RCT of Riluzole?

Not much of a correlate between dose and effect of drug.

With increasing dose, there was not an increased life expectancy

Only a small increase in life expectancy between drug and placebo


Why is there no good drug for MND?

The fundamental causes of the diseases are not known


What are the causes of MND?

90% of cases are sporadic

The 10% that aren't:
1. Genetic factors:
Mutations in various genes:
• SOD1
• TDP43
• Angiogenin
• Optineurin
It is unclear whether the mutations are loss or gain of function

2. Environmental factors:
• Head trauma
• Military service (Gulf war)
• Chemical toxins


What are some biochemical observations in MND?

NB not just motor neurons, but astrocytes & microglia as well

• Impaired glutamate uptake from synapse


Discuss in general mutations in Cu/Zn superoxide dismutase

Gene known to be commonly mutated in MND
Still not known how this affects pathogenesis


What is Cu/Zn superoxide dismutase (SOD)?

(detoxifies reactive oxygen species in cells)

Found in every cell in the body

Superoxide → Hydrogen peroxide → water


What is the structure of SOD?

150 aa long
Binds one Cu and one Zn atom


What sort of mutations in SOD1 cause MND?

Substitution → toxic gain of function


What are the proposed toxic gain of function mechanisms of SOD?

Toxic gain of function mutation that we still don't know about:
• Aberrant pro-oxidant GoF
• Protein mis-folding
• Protein aggregation
• Mitochondrial dysfunction


Describe the genetic component of MND

90% are sporadic → not familial

10% familial
• Family history present
• Specific genes:
- SOD1
- Optineurin


Curious research questions ?

1. The genes identified as mutated in MND are all very different, but they cause the same disease

2. The mutations are in genes whose products are important around the body, but they only seem to affect motor neurons


What is the inheritance of the mutations in MND?

Most are autosomal dominant


What are some models being used to research MND?

1. Tissue biopsies from people who have died from MND
• Difficult to come by

2. Mouse models
• Allows create a genetic model of the disease
• Can induce mice to get MND through specific mutations


What is seen with more and more mutant SOD1 in mice models?

More severe motor neurone pathology → more severe phenotype

However, this has recently been disproved in studies in mice
The drug used in mice with SOD1 mutation increased the levels of mutant SOD


What is seen in mice locomotor function in current studies?

Rotator rod, mice can stay on it

1. Normal mice:
• stays on rod for 150 sec throughout its life

2. SOD1 mutation; no drug
• rapid decrease in ability to stay on rod
• At 30 weeks, hind limbs are practically paralysed

3. SOD1 mutation + drug
• Progressive decrease in time able to stay on rod
• Less rapid decrease than without the drug


What is seen in life expectancy in mice models?

1. SOD1 mutation + no drug
• Quicker progression to death

2. SOD1 mutation + drug
• Increased survival period


What is seen in motor neurons in mice model studies?

1. SOD1 mutation + no drug
• fewer alpha motor neurons

2. SOD1 mutation + drug
• protection of motor neurons


What is seen in terms of oxidatively modified proteins in mice model studies?

1. SOD1 mutation + no drug
• Large load of oxidatively modified proteins

2. SOD1 mutation + drug
• relatively normal amount


What is seen in terms of SOD activity in mice model studies?

1. SOD1 mutation + no drug
• Increased SOD activity

2. SOD1 mutation + drug
• Increased SOD activity
• Greater activity than w/o drug

→ Drug increases SOD activity further


What is seen in terms of inflammation in mice model studies?

Increased inflammation in CNS due to infiltration of astrocytes


What is the effect of the drug on levels of mutant SOD?

Drug → increased levels of mutant SOD

This is a confusing result

This has negated the dogma that "more mutant SOD → more severe phenotype"


What are the various forms of SOD?

Which is the toxic form?

Three different states

1. Holo:
• Functional form
• Zn and Cu present

2. Metal deficient
• Cu or Zn present

3. Apo
• neither Zn or Cu present

Toxic form:
• Metal deficient form
• Apo form degraded very quickly in the body


What is the effect of this new drug (as yet undisclosed) on SOD?

Driving the toxic form of the protein to a non-toxic, functional form

• The drug contains Cu
• Drug delivers copper to the spinal cord
• The Cu is donated to SOD to make it functional


Discuss the stability of the holo form of SOD

Very very stable
• SOD synthesised in cell body (in spinal cord) and must travel all the way down the axon, thus, needs to be stable


Describe radioactive Cu isotopes

1. Radioactively labelled Cu isotopes administered to person
2. PET scanning of person
3. Cu transfer only occurs if the SOD is metal deficient, i.e. if disease is present

i.e. Increased Cu transfer in the spinal cord of rats with MND

This is a potential diagnostic tool


Which three key questions, which are as yet unanswered, are basic researchers trying to address?

1. Cause of the disease

2. Diagnosis of the disease

3. Treatment of the disease