Amyotrophic Lateral Sclerosis

Question 1

Define amyotrophic lateral sclerosis

Answer 1

A rapidly progressive and fatal neurodegenerative motor disorder causing muscle wasting, paralysis, and death

Question 2

What is the most common cause of death in ALS?

Answer 2

Respiratory failure

Question 3

Define lateral sclerosis

Answer 3

Scarring of the corticospinal tracts

Question 4

State the incidence and prevalence of ALS

Answer 4

Incidence 2 per 100,000 population, and prevalence 5-8 per 100,000

Question 5

State the lifetime risk of developing ALS in the UK for males and females

Answer 5

Males: 5.1 per 1,000
Females: 3 per 1,000

Question 6

What characteristics do the neurons typically affected by ALS share?

Answer 6

They tend to have long axons which are very active with very high energy demands due to the transfer of proteins and other molecules

Question 7

Give two classic presenting signs

Answer 7

Wasting of the thenar hand muscles at the base of the thumb, or wasting of the tongue muscle

Question 8

Give two classic areas where symptoms start

Answer 8

The distal muscles of a single limb, or in the bulbar system

Question 9

State some of the symptoms of ALS

Answer 9

Muscle atrophy, spasticity, muscle weakness, speech and swallowing deficits, eventual paralysis of skeletal muscles

Question 10

In what percentage of patients is cognitive function affected?

Answer 10

15%

Question 11

Give 2 early diagnostic tests

Answer 11

Muscle biopsy and electromyography

Question 12

What will electromyography show?

Answer 12

Motor unit degradation, initially associated with sprouting of the surviving motor neurons and re-innervation

Question 13

What will muscle biopsy show?

Answer 13

Stained for ATPase, it will show grouped atrophic fibres (not unique to ALS)

Question 14

Give 3 lower motor neuron signs and 3 upper motor neuron signs of ALS

Answer 14

LMN signs: muscle weakness, muscle wasting, fasciculations, cramps
UMN signs: stiffness, slow movement, slow clumsy speech, Babinski sign

Question 15

Name 2 differential diagnoses

Answer 15

Progressive bulbar palsy and primary lateral sclerosis

Question 16

Describe progressive bulbar palsy

Answer 16

A neurodegenerative disease affecting the brainstem and the nerves supplying the bulbar muscles - involved in speech, swallowing, and chewing. It is more common in older females and mean suvival is 0.5-3 years

Question 17

Describe primary lateral sclerosis

Answer 17

A neurodegenerative disease that primarily affects upper motor neurons, causing spasticity and hyperreflexia. Mean survival is 20 years

Question 18

Describe the management of ALS

Answer 18

Speech and swallowing assictance, occupational therapy, breathing assistance (oxygen then assisted ventilation), and symptomatic treatment for cramps and spasms. The drug Riluzole extends survival by around 3 months

Question 19

Describe 3 characteristic features of ALS pathology

Answer 19

1) Motor neuron loss in the spinal cord, brainstem, and motor cortex
2) Corticospinal tract degeneration
3) Ubiquitinated inclusions in neuronal cell bodies and proximal axons

Question 20

Describe the appearance of corticospinal tract degeneration

Answer 20

Pallor in the lateral columns of the spinal cord, with some ventral pallor from uncrossed corticospinal pathways

Question 21

What is the function of ubiquitination?

Answer 21

It marks the protein out for degradation by the ubiquitin proteasome system

Question 22

What is ubiquitin?

Answer 22

A small regualatory protein of 76 amino acids

Question 23

How is ubiquitin added to proteins?

Answer 23

Post-translational modification

Question 24

Describe the role of TDP-43 in ALS

Answer 24

TDP-43 is a major component of ubiquitinated inclusions, present in 97% of ALS cases

Question 25

What percentage of ALS cases have a familial element?

Answer 25

10%

Question 26

Name 3 protein groups associated with ALS mutations

Answer 26

RNA binding proteins, proteostatic proteins, and cytoskeletal proteins

Question 27

Name 3 major proteins with ALS mutations

Answer 27

Superoxide dismutase 1 (SOD1), TDP-43, fused in sarcoma (FUS)

Question 28

Why can these ALS mutations be carried and passed on without leading to disease development?

Answer 28

Despite being autosomal dominant, they have incomplete penetrance. Age of onset is also controlled by other factors

Question 29

Which gene encodes TDP-43?

Answer 29

Trans-activating response DNA binding protein (TARDBP)

Question 30

What is the function of TDP-43?

Answer 30

It binds trans-activating response DNA sequences in DNA and RNA to repress transcription, as well as inhibiting splicing and regulating mRNA transport and local translation

Question 31

How do TDP-43 mutations affect TDP-43?

Answer 31

They lead to its cleavage, causing it to relocate to the cytoplasm, where it is hyperphosphorylated and forms ubiquitinated aggregates in motor neurons, glia, and neurites

Question 32

How are ALS patients with FUS mutations different to those with TDP-43 mutations?

Answer 32

They develop FUS-positive inclusions instead of TDP-43 inclusions

Question 33

What is FUS?

Answer 33

A transcritpional activator that acts on nuclear hormone receptors and NFkappaB at the RNA polymerase complex. It is part of the spliceosome machinery

Question 34

Where are 82% of ALS-causing FUS mutations located?

Answer 34

Introns (non-coding regions)

Question 35

How does cell stress affect FUS?

Answer 35

It stimulates its efflux to the cytoplasm, where it enters RNA transport granules to conserve mRNAs

Question 36

Describe the effect of FUS knockout in mice

Answer 36

They have reduced dendritic spine formation

Question 37

Name the FUS nuclear transport protein

Answer 37

Transportin

Question 38

Name the TDP-43 nuclear transport protein

Answer 38

Importin

Question 39

How does TDP-43 affect dendrites?

Answer 39

It is a regular of local dendritic protein synthesis and responsible for long-term potentiation

Question 40

Why does mutated FUS accumulate in the cytoplasm?

Answer 40

Loss of the nuclear localisation signal and inhibition of transportin

Question 41

What did Mihevc et al’s 2016 research into TDP-43 transgenic mice with a defective nuclear localisation signal show?

Answer 41

Accumulation of insoluble, phosphorylated TDP-43 in the brain and spinal cord, loss of endogenous TDP-43, brain atrophy, muscle denervation, dramatic motor loss, and progressive motor impairments leading to death

Question 42

Why are the effects on nuclear transport proteins in familial ALS relevent to sporadic ALS?

Answer 42

The abundance of nuclear transport proteins decreases with age, which could lead to increased cytoplasmic TDP-43. This, combined with cell stress, could lead to the formation of TDP-43 and FUS-containing stress granules in the cytoplasm - the precursors of large TDP-43 inclusions