Lecture 22 - Motor Neurone Disease Flashcards
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
- 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
Generally:
• 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?
Riluzole
• 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 etc. It is unclear whether the mutations are loss or gain of function
- 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
Astrocytes:
• 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)?
Antioxidant:
(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 etc.
Curious research questions ?
- The genes identified as mutated in MND are all very different, but they cause the same disease
- 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?
- Tissue biopsies from people who have died from MND
• Difficult to come by - 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
- Normal mice:
• stays on rod for 150 sec throughout its life - SOD1 mutation; no drug
• rapid decrease in ability to stay on rod
• At 30 weeks, hind limbs are practically paralysed - 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?
- SOD1 mutation + no drug
• Quicker progression to death - SOD1 mutation + drug
• Increased survival period
What is seen in motor neurons in mice model studies?
- SOD1 mutation + no drug
• fewer alpha motor neurons - SOD1 mutation + drug
• protection of motor neurons
What is seen in terms of oxidatively modified proteins in mice model studies?
- SOD1 mutation + no drug
• Large load of oxidatively modified proteins - SOD1 mutation + drug
• relatively normal amount
What is seen in terms of SOD activity in mice model studies?
- SOD1 mutation + no drug
• Increased SOD activity - 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
- Holo:
• Functional form
• Zn and Cu present - Metal deficient
• Cu or Zn present - 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
Mechanism:
• 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
Why?
• 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
- Radioactively labelled Cu isotopes administered to person
- PET scanning of person
- 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?
- Cause of the disease
- Diagnosis of the disease
- Treatment of the disease
