ALS Flashcards
Describe ALS
Rapidly progressive and fatal neurodegenerative disease of death of MNs
ALS is most common MND
Develops at ages 40-70
What are the 3 classifications of ALS/MND?
Sporadic; 90-95% of cases. Random, no cause
Familial; inherited, 5-10%
Guamanian; high incidence of ALS was observed in guam in 1950s
Describe the onset of ALS
Limbs; weakening of grip, decreased dexterity, foot drop, leg stiffness, tripping
Throat; slurred speech, difficulty chewing or swallowing
Describe the progression of ALS
Limbs; unable to hold objects, write, feed or toilet, unable to walk, stand or turn in bed
Throat; impaired swallow
Breathing; breathless with exertion or lying flatt
Cognition; dementia rare but subtle deficits
What is the average life expectancy of ALS from diagnosis?
Average of 22 months
What is a motor neuron?
Specialised nerve cells in brain and spinal cord which transmit electrical signals to muscle for generation of movement
What are the 2 different types of motor neurons?
UMN; motor cortex and travel down spinal cord to connect with LMNs
LMNs; travel out with spinal cord to connect to muscle
Describe the clinical signs of MND in respect to the location of degeneration
Pre-motor; difficulty planning and initiating movement
UMN; modest weakness, stiffness, spasticity, hyperreflexia, extensor plantar response
LMN; major weakness, muscle wasting, fasciculation
Cognition; subtle deficits in 30% of patients including verbal fluency, executive function
Spares; eye movement, bladder and bowel control
How is MND/ALS diagnosed?
No simple diagnostic test
Diagnosis of exclusion
EMG/ nerve conduction utilised
Average of 12 months after symptom initiation
Describe the pathological changes within neurons seen in MND?
Protein inclusions within motor neurons and surrounding astrocytes
Why do people with MND develop paralysis?
Pyramidal motor neurons in frontal lobe degenerate and die causing severe spasticity and mild weakness of muscle groups
Motor neurons in spinal cord degenerate and die causing wasting and major weakness
Results in complete muscle paralysis; no linkage between motor neurons and muscles
What are 2 key proteins that have been identified as having mutations linked to MND?
TDP-43
FUS
Describe the most common gene defects in MND?
C9orf72 (24% of all gene targets in MND)
SOD1 (20%)
FUS (5%)
TDP43 (5%)
How does gene testing help MND patients?
Why the disease occurred
Excludes the presence of gene mutations - if family history
IVF and gene testing
Why do we focus on familial MND when the population effect is small?
Huge biological impact
Only 1 in 10 people with MND have a FMHx of MND
MND-causing gene mutations can be used to model disease
Allows studying of disease mechanisms and development of novel therapies
In terms of genetic abnormalities; why do the motor neurons degenerate?
TDP-43 accumulates in the cell body of motor neurons in 95% of all genetically linked MND cases
TDP-43 resides in nucleus where is binds to DNA and involved in transcription
In ALS; TDP-43 aberrantly accumulated in the cytoplasm where it forms aggregates
Changes from a nuclear protein to a cytoplasmic protein
What animal model has been utilised to model TDP-43 toxicity in ALS?
Chick spinal neurons
Expression of WT and TDP-43 mutant proteins causes toxicity in chick embryonic motor neurons in vivo
What do neurons that express TDP-43 mutant forms display?
Cytoplasmic aggregates
Reduction in axonal length
Cellular toxicity
Which animal models are used in ALS?
Zebrafish - swimming abnormalities
Drosophila - flying abnormalities
Mouse - abnormal stature, can look at motor evoked potentials within the muscle (reduced in TDP-43 mutant mice)
Describe SOD1 in its pathogenesis of ALS
Protein Cu/Zn superoxide dismutase
Most common is alanine-valanine of SOD1 (A4V)
Aggressive course; survival of 12 months
Mice and rats expressing mutant SOD1 develop MND
Mutant SOD1 is a key component of protein that aggregates
Describe the molecular mechanisms by which SOD-1 results in ALS
Converts superoxide radials to hydrogen peroxide and oxygen
Metalloprotein (protein with metal ion co-factor) and is a key enzyme in anti-oxidation
Where is SOD-1 found in the neuron?
Cell cytosol, nucleus and mitochondrial membrane