Amyotrophic Lateral Sclerosis Flashcards
Describe the clinical features of ALS and the physiological basis for these disease-associated pathologies Describe the neuropathological hallmarks of ALS including the role of TDP-43 positive ubiquitinated protein inclusions and their contribution to other neurodegenerative conditions such as frontotemporal lobar degeneration (FTLD) Assess the importance of identifying mutations in the familial form of ALS (FALS) in understanding the common pathogenic mechanisms underlying familial and sporadic
Define amyotrophic lateral sclerosis
A rapidly progressive and fatal neurodegenerative motor disorder causing muscle wasting, paralysis, and death
What is the most common cause of death in ALS?
Respiratory failure
Define lateral sclerosis
Scarring of the corticospinal tracts
State the incidence and prevalence of ALS
Incidence 2 per 100,000 population, and prevalence 5-8 per 100,000
State the lifetime risk of developing ALS in the UK for males and females
Males: 5.1 per 1,000
Females: 3 per 1,000
What characteristics do the neurons typically affected by ALS share?
They tend to have long axons which are very active with very high energy demands due to the transfer of proteins and other molecules
Give two classic presenting signs
Wasting of the thenar hand muscles at the base of the thumb, or wasting of the tongue muscle
Give two classic areas where symptoms start
The distal muscles of a single limb, or in the bulbar system
State some of the symptoms of ALS
Muscle atrophy, spasticity, muscle weakness, speech and swallowing deficits, eventual paralysis of skeletal muscles
In what percentage of patients is cognitive function affected?
15%
Give 2 early diagnostic tests
Muscle biopsy and electromyography
What will electromyography show?
Motor unit degradation, initially associated with sprouting of the surviving motor neurons and re-innervation
What will muscle biopsy show?
Stained for ATPase, it will show grouped atrophic fibres (not unique to ALS)
Give 3 lower motor neuron signs and 3 upper motor neuron signs of ALS
LMN signs: muscle weakness, muscle wasting, fasciculations, cramps
UMN signs: stiffness, slow movement, slow clumsy speech, Babinski sign
Name 2 differential diagnoses
Progressive bulbar palsy and primary lateral sclerosis
Describe progressive bulbar palsy
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
Describe primary lateral sclerosis
A neurodegenerative disease that primarily affects upper motor neurons, causing spasticity and hyperreflexia. Mean survival is 20 years
Describe the management of ALS
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
Describe 3 characteristic features of ALS pathology
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
Describe the appearance of corticospinal tract degeneration
Pallor in the lateral columns of the spinal cord, with some ventral pallor from uncrossed corticospinal pathways
What is the function of ubiquitination?
It marks the protein out for degradation by the ubiquitin proteasome system
What is ubiquitin?
A small regualatory protein of 76 amino acids
How is ubiquitin added to proteins?
Post-translational modification
Describe the role of TDP-43 in ALS
TDP-43 is a major component of ubiquitinated inclusions, present in 97% of ALS cases
What percentage of ALS cases have a familial element?
10%
Name 3 protein groups associated with ALS mutations
RNA binding proteins, proteostatic proteins, and cytoskeletal proteins
Name 3 major proteins with ALS mutations
Superoxide dismutase 1 (SOD1), TDP-43, fused in sarcoma (FUS)
Why can these ALS mutations be carried and passed on without leading to disease development?
Despite being autosomal dominant, they have incomplete penetrance. Age of onset is also controlled by other factors
Which gene encodes TDP-43?
Trans-activating response DNA binding protein (TARDBP)
What is the function of TDP-43?
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
How do TDP-43 mutations affect TDP-43?
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
How are ALS patients with FUS mutations different to those with TDP-43 mutations?
They develop FUS-positive inclusions instead of TDP-43 inclusions
What is FUS?
A transcritpional activator that acts on nuclear hormone receptors and NFkappaB at the RNA polymerase complex. It is part of the spliceosome machinery
Where are 82% of ALS-causing FUS mutations located?
Introns (non-coding regions)
How does cell stress affect FUS?
It stimulates its efflux to the cytoplasm, where it enters RNA transport granules to conserve mRNAs
Describe the effect of FUS knockout in mice
They have reduced dendritic spine formation
Name the FUS nuclear transport protein
Transportin
Name the TDP-43 nuclear transport protein
Importin
How does TDP-43 affect dendrites?
It is a regular of local dendritic protein synthesis and responsible for long-term potentiation
Why does mutated FUS accumulate in the cytoplasm?
Loss of the nuclear localisation signal and inhibition of transportin
What did Mihevc et al’s 2016 research into TDP-43 transgenic mice with a defective nuclear localisation signal show?
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
Why are the effects on nuclear transport proteins in familial ALS relevent to sporadic ALS?
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
