ALS "Lou Gehrig's Disease" (Kerr) Flashcards
Who first characterized ALS?
Jean-Martin Charcot
ALS is a(n) _______-onset, neurodegenerative disease that preferentially affects _________________.
adult; upper and lower motoneurons
What are the main characteristic symptoms of ALS?
- progressive muscle weakness
- atrophy
- spasticity
When does death occur after diagnosis of ALS?
within 3-5 years
What is the global incidence of ALS? Does it have high/low incidence/prevalence?
- 2/100,000
- high incidence
- low prevalence
What is the approximate age of onset for ALS?
~55 years of age
TRUE or FALSE: ALS leads to degeneration of the motoneuron only
FALSE: the entire motor unit (motoneuron and muscle fibers that it innervates)
What are the different motor unit types? What kind of metabolism do each of them use? Which motor neurons are each of the units associated with? Which one has the largest muscle fibers?
- slow (S) - oxidative metabolism; type I
- fast fatigue resistant (FR) - glycolytic and oxidative metabolism; type IIA
- fast fatigue (FF) - glycolytic metabolism; type IIB –> LARGEST fibers
What are some known risk factors for ALS?
- age
- gender 1.5:1 male:female
- family history - 20% familial
What are some possible risk factors for ALS?
- athleticism
- exposure to heavy metals/herbicides/chemicals
- smoking
- trauma (consistent/persistent head trauma)
- gulf war service
What is the difference between bulbar and spinal ALS? Which one is more common?
- bulbar affects swallowing and speaking
- spinal causes weakness in one distal limb; more common
TRUE or FALSE: for a diagnosis of ALS, only lower motoneurons signs must be present
FALSE: both upper and lower motoneuron
TRUE or FALSE: ALS symptoms must be present in 1 or 4 body segments to be diagnosed
FALSE: must be present in 3 of 4
What are the upper motoneuron symptoms?
- moderate weakness
- hyperreflexia
- pathological reflexes
- pseudobulbar affect
- spasticity
- loss of dexterity
- slowed movements
What are the lower motoneuron symptoms?
- severe weakness
- hyporeflexia
- muscle atrophy
- fasciculations
- muscle cramps
- muscle hypotonicity or flaccidity
10-20% of fALS cases are associated with _____________ mutations to the _________________ gene that transcribes _______________.
autosomal dominant; superoxide dismutase (SOD1); sarcoplasmic Cu/Zn SOD1
What is the most common mutation of SOD?
A4V
Describe the SOD1 mouse experiment for familial ALS.
- G93A SOD1 mouse
- lives for 130 days
- symptoms at 90 days
- loss of motoneurons from lumbar spinal cord
What is normal SOD1 function? Draw the pathway.
- breaks down free radicals like superoxide
- slide 15 pathway
TRUE or FALSE: toxicity in ALS is associated with levels of SOD1 enzyme activity
FALSE: NOT associated with SOD1 enzyme; TBD GAIN of cytotoxic function
Which motoneurons are not affected in ALS? Why?
- Onuf’s nucleus
- oculomotor nucleus
- b/c they have Ca buffering proteins, calbindin and parvalbumin (Ca is neurotoxic in excess)
How is Ca neurotoxic in excess?
- can initiate cascade of cell death by activating caspases
- can overwhelm Ca buffering systems, causing energy deficits
What is the first clue into ALS disease progression?
Ca2+ influx may play a role in triggering motoneuron death
What are the causes of motoneuron death in ALS?
- protein aggregation
- cytoskeletal derangement
- inflammation
- glutamatergic excitotoxicity
- oxidative stress
ALL CONTRIBUTE TO NEURODEGENERATION AND DEATH
Describe protein aggregation in ALS.
- aberrant folding of mSOD1 proteins (monomers and dimers) aggregate
- loss of function
- chaperone activity reduced
- proteosome activity reduced
Describe soma, dendrites, and axons in the healthy CNS (e.g. synapses, receptors, transporters, etc.).
SOMA and DENDRITES:
- glutamatergic synapses
- NMDA and AMPA receptors
- functioning intracellular chaperone and proteosomes
- Glu transporters
AXON:
- axonal transport
- ACh release at NMJ
Describe cytoskeletal derangement in ALS.
- mSOD1 aggregates and choke chaperones and proteosomes, AFFECTING BOTH CELLS –> inhibit transport
- NEUROFILAMENT DISORGANIZATION and accumulation, associated with hyperphosphorylation due to oxidative stress
Describe inflammation in ALS.
- asymptomatic stage, little to no T cells
- early stage, T cells protective response
- end stage, T cells accumulate detrimental effects (Cytotoxic)
Describe the role of microglia and astrocytes in contributing to ALS (i.e. reactive gliosis).
MICROGLIA:
- accumulate in regions of diseased motoneurons
- release inflammatory cytokines, glutamate, free radicals
ASTROCYTES:
- release glutamate
i.e. cytokines and excess glutamate
What is excitotoxicity?
phenomenon whereby excitatory action of glutamate and related excitatory AAs transform into neuropathological process that can rapidly kill CNS neurons
What is the normal function of GluR2R subunit?
- post transcriptional modification of mRNA for one AA: glutamine to arginine (Q to R) in the GluR2 subunit
- low Ca2+ permeability
What happens to the GLuR2R subunit in ALS?
- becomes unedited GluR2Q isoform
- highly permeable to Ca2+
WHat are EAATs? Where are EAAT1 and EAAT2 found? How does ALS affect EAATs?
- regulate levels of glutamate at the synapse
- EAAT1 and EAAT2 in astrocytes
- ALS triggers downregulation
Describe how loss of EAATs (e.g. in ALS) leads to excitotoxicity.
- glutamate accumulates in the synapse
- leads to high intracellular Ca+
- no Ca2+ binding proteins: calbindin and calmodulin
Which protein family do TDP-43 and FUS belong to? What are their function?
- hnRNP protein family
- regulate RNA metabolism
- bind thousands of RNA
What is a hallmark feature of ALS? What other pathologies does this feature indicate?
- TDP-43
- cytoplasmic inclusions of TDP-43 also feature FTD, PD, and AD
What are the effects of TDP-43?
- transcriptional regulation
- stress granules
- alternative splicing
- mRNA transport
- nucleus-cytoplasm shuttling
- microRNA processing
What was the first identified genetic link between familial FTD and ALS?
c9orf72
What do intronic expansions in c9orf72 do? What is the mechanism of C9orf72? What does inactivation of C9orf72 lead to? Where are the inclusions?
- intronic expansion interferes with normal protein expression
- mechanism unclear - encodes guanine exchanger for G proteins
- inactivation –> abnormal microglia function and neuroinflammation
- intranuclear RNA foci and cytoplasmic inclusions
