L1 Motor Neuron Disease

Question 1

What does ALS stand for and what is it also commonly known as?

Answer 1

Amyotrophic Lateral Sclerosis. Commonly known as MND.

Question 2

What is MND characterised by and who first described it?

Answer 2

Progressive degeneration of motor neurons in the brain and spinal cord. It is a heterogenous disease that affects both upper and lower motor neurons.

It was first described by Jean-Martin Charcot.

Question 3

What is the life expectancy of MND?

Answer 3

Between 2-4 years, but 10% survive for 10 years.

Question 4

What are the roles of the upper and lower motor neurons?

Answer 4

• The upper motor neurons modulate and decide which muscles are contracting and relaxing.
• The lower motor neurons go into the muscles and tell them to contract.

Question 5

Describe primary lateral sclerosis and primary muscular atrophy.

Answer 5

• Primary lateral sclerosis is the degeneration of corticospinal motor neurons (descending axons in which the lateral spinal cord seem scarred) i.e. upper motor neurons (UMNs).
• Primary muscular atrophy is a neurodegeneration of spinal motor neurons with secondary denervation and muscle wasting i.e. lower motor neurons (LMN).

Question 6

What are the three types of onset of MND? Describe them.

Answer 6

• Limb onset (75% of cases). Muscle weakness in the legs, wasting and fasciculations (muscle twitches).
• Bulbar onset (20% of cases). Dysarthria (abnormally sounding voice), dysphasia (cannot swallow) and oropharyngeal muscle weakness.
• Respiratory onset (5% of cases). Reduced appetite, weight loss, sleep disturbance and fatigue.

This then progresses to almost complete skeletal muscular paralysis.

Question 7

What is MND also associated with?

Answer 7

• Frontotemporal dementia (language or behavioural variant).
• Cognitive problems.
• Parkinsonism.
• ANS problems (blood pressure or skin temperature).
• Hippocampus, Substantia Nigra.

Question 8

What does an autopsy of ALS patients show?

Answer 8

• Degeneration of motor neurons in the motor cortex.
• Brainstem motor nuclei degeneration.
• Degeneration of anterior horns in the spinal cord.

Question 9

What happens to spinal motor neurons as the disease progresses?

Answer 9

They shrink and accumulate rounded or thread-like deposits of aggregated proteins called (inclusions).

These cytoplasmic inclusions often become ubiquitinated.

The TAR-DNA binding protein (TDP-43) forms the major component of ubiquitinated inclusions in most cases of ALS.

Question 10

What is the most important gene in MND and why?

Answer 10

C9ORF72 because it is responsible for 50% of genetic MND cases. It causes either reduced or abnormal transcription of a protein.

Note this is an INTRON not specifically a gene.

Question 11

What is the 5-step process for developing MND?

Answer 11

This applies to the 90% of people that have no genetic mutation yet have MND.

The 5-step process are the potential factors that are contributing to MND. These include:

1) Smoking
2) Mutations in the neurons themselves.
3) Military background.
4) Lots of exercise.

Question 12

What was the first molecular discovery of MND?

Answer 12

In 1993, dominant mutations in SOD1. This is a major antioxidant with normal functions of catalytically converting highly reactive superoxide to either hydrogen peroxide or oxygen.

However, there is still no firm conclusion as to whether the mutant SOD1 is a primary cause of MND.

Question 13

What is the correlation between protein aggregation and MND?

Answer 13

Both mutations in SOD1 and TDP-43 lead to protein aggregates, which indicates a link between protein aggregates and the disease.

However, neither have been shown to be the driving cause of the disease and their elimination fails to effect any aspect of MND in mice.

Question 14

List the 6 hypothesised pathologies of MND.

Answer 14

• Disturbances in protein quality control.
• Hyperactivation of microglia triggers inflammation and degeneration in motor neurons.
• Diminished energy supply from reduction in MCT1 transporters (lactate transporters).
• Cytoskeletal defects and altered axonal transport.
• Disturbances in RNA metabolism.
• Excitotoxicity from reduced glutamate uptake.

Question 15

Explain the role of mutant SOD1 in microglia.

Answer 15

Microglia become activated in all instances of ALS and the synthesis of SOD1 is a key determinant of rapid disease progression.

This was determined after selectively silencing SOD1 within microglia.

Question 16

What are alternative diagnoses for they symptoms of MND?

Answer 16

• Anterior horn cells = Spinomuscular atrophy, polio.
• Motor nerves = Neuropathies.
• Muscles = Myasthenia gravis, muscular dystrophies.
• Other neurogenerative diseases = FTD, Parkinson’s disease.

Question 17

What are alternative diagnoses for they symptoms of MND?

Answer 17

• Anterior horn cells = Spinomuscular atrophy, polio.
• Motor nerves = Neuropathies.
• Muscles = Myasthenia gravis, muscular dystrophies.
• Other neurogenerative diseases = FTD, Parkinson’s disease.

Question 18

List five treatments for MND. What is the main aim of these treatments?

Answer 18

1) Riluzole
2) Non-invasive ventilation (NIV) - people using this live on average 7 months longer.
3) Nutrition
4) Carer support
5) Multi-disciplinary specialist care

The aim of these treatments is to improve quality of life.

Question 19

What happens to MND patients when they have respiratory problems? How are these treated?

Answer 19

They get nocturnal respiratory insufficiency. This is where you get frequent nocturnal awakening, nocturia, unrefreshed sleep, morning headaches, daytime sleepiness, poor appetite, lethargy, weight loss and loss of strength.

This is treated with respiratory masks.

Question 20

What is diaphragm pacing?

Answer 20

This is where wires are inserted under the diaphragm to stimulate the diaphragm to contract. Patients use this for several hours a day in the attempt to strengthen the muscles so they can contract by themselves.

Question 21

What are the three experimental methods that have been used to model SOD1-related MND?

Answer 21

1) Cellular models.
2) Mouse and Zebrafish models.
3) Human disease biosamples.

Question 22

What have gene silencing experiments shown?

Answer 22

This is where a viral vector andenovirus scAAV9 crosses the blood-brain barrier and produces fast, robust and long-lasting gene-transfer in spinal motor neurons.

In vitro experiments have shown more than 80% knock-down of SOD1 expression.

Question 23

Whlat are antisense oligonucleotides (ASOs) and how do they work?

Answer 23

ASOs are modified short synthetic nucleic acids that are stable in the brain and have increased binding potency. They bind to target mRNAs and promote degradation by RnaseH.

However, the intrathecal administration of this treatment is extremely unpleasant.