ALS "Lou Gehrig's Disease" (Kerr)

Question 1

Who first characterized ALS?

Answer 1

Jean-Martin Charcot

Question 2

ALS is a(n) _______-onset, neurodegenerative disease that preferentially affects _________________.

Answer 2

adult; upper and lower motoneurons

Question 3

What are the main characteristic symptoms of ALS?

Answer 3

• progressive muscle weakness
• atrophy
• spasticity

Question 4

When does death occur after diagnosis of ALS?

Answer 4

within 3-5 years

Question 5

What is the global incidence of ALS? Does it have high/low incidence/prevalence?

Answer 5

• 2/100,000
• high incidence
• low prevalence

Question 6

What is the approximate age of onset for ALS?

Answer 6

~55 years of age

Question 7

TRUE or FALSE: ALS leads to degeneration of the motoneuron only

Answer 7

FALSE: the entire motor unit (motoneuron and muscle fibers that it innervates)

Question 8

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?

Answer 8

• 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

Question 9

What are some known risk factors for ALS?

Answer 9

• age
• gender 1.5:1 male:female
• family history - 20% familial

Question 10

What are some possible risk factors for ALS?

Answer 10

• athleticism
• exposure to heavy metals/herbicides/chemicals
• smoking
• trauma (consistent/persistent head trauma)
• gulf war service

Question 11

What is the difference between bulbar and spinal ALS? Which one is more common?

Answer 11

• bulbar affects swallowing and speaking
• spinal causes weakness in one distal limb; more common

Question 12

TRUE or FALSE: for a diagnosis of ALS, only lower motoneurons signs must be present

Answer 12

FALSE: both upper and lower motoneuron

Question 13

TRUE or FALSE: ALS symptoms must be present in 1 or 4 body segments to be diagnosed

Answer 13

FALSE: must be present in 3 of 4

Question 14

What are the upper motoneuron symptoms?

Answer 14

• moderate weakness
• hyperreflexia
• pathological reflexes
• pseudobulbar affect
• spasticity
• loss of dexterity
• slowed movements

Question 15

What are the lower motoneuron symptoms?

Answer 15

• severe weakness
• hyporeflexia
• muscle atrophy
• fasciculations
• muscle cramps
• muscle hypotonicity or flaccidity

Question 16

10-20% of fALS cases are associated with _____________ mutations to the _________________ gene that transcribes _______________.

Answer 16

autosomal dominant; superoxide dismutase (SOD1); sarcoplasmic Cu/Zn SOD1

Question 17

What is the most common mutation of SOD?

Answer 17

A4V

Question 18

Describe the SOD1 mouse experiment for familial ALS.

Answer 18

• G93A SOD1 mouse
• lives for 130 days
• symptoms at 90 days
• loss of motoneurons from lumbar spinal cord

Question 19

What is normal SOD1 function? Draw the pathway.

Answer 19

• breaks down free radicals like superoxide
• slide 15 pathway

Question 20

TRUE or FALSE: toxicity in ALS is associated with levels of SOD1 enzyme activity

Answer 20

FALSE: NOT associated with SOD1 enzyme; TBD GAIN of cytotoxic function

Question 21

Which motoneurons are not affected in ALS? Why?

Answer 21

• Onuf’s nucleus
• oculomotor nucleus
• b/c they have Ca buffering proteins, calbindin and parvalbumin (Ca is neurotoxic in excess)

Question 22

How is Ca neurotoxic in excess?

Answer 22

• can initiate cascade of cell death by activating caspases
• can overwhelm Ca buffering systems, causing energy deficits

Question 23

What is the first clue into ALS disease progression?

Answer 23

Ca2+ influx may play a role in triggering motoneuron death

Question 24

What are the causes of motoneuron death in ALS?

Answer 24

1. protein aggregation
2. cytoskeletal derangement
3. inflammation
4. glutamatergic excitotoxicity
5. oxidative stress

ALL CONTRIBUTE TO NEURODEGENERATION AND DEATH

Question 25

Describe protein aggregation in ALS.

Answer 25

- aberrant folding of mSOD1 proteins (monomers and dimers) aggregate - loss of function - chaperone activity reduced - proteosome activity reduced

Question 26

Describe soma, dendrites, and axons in the healthy CNS (e.g. synapses, receptors, transporters, etc.).

Answer 26

SOMA and DENDRITES: - glutamatergic synapses - NMDA and AMPA receptors - functioning intracellular chaperone and proteosomes - Glu transporters AXON: - axonal transport - ACh release at NMJ

Question 27

Describe cytoskeletal derangement in ALS.

Answer 27

1. mSOD1 aggregates and choke chaperones and proteosomes, AFFECTING BOTH CELLS --> inhibit transport 2. NEUROFILAMENT DISORGANIZATION and accumulation, associated with hyperphosphorylation due to oxidative stress

Question 28

Describe inflammation in ALS.

Answer 28

1. asymptomatic stage, little to no T cells 2. early stage, T cells protective response 3. end stage, T cells accumulate detrimental effects (Cytotoxic)

Question 29

Describe the role of microglia and astrocytes in contributing to ALS (i.e. reactive gliosis).

Answer 29

MICROGLIA: - accumulate in regions of diseased motoneurons - release inflammatory cytokines, glutamate, free radicals ASTROCYTES: - release glutamate i.e. cytokines and excess glutamate

Question 30

What is excitotoxicity?

Answer 30

phenomenon whereby excitatory action of glutamate and related excitatory AAs transform into neuropathological process that can rapidly kill CNS neurons

Question 31

What is the normal function of GluR2R subunit?

Answer 31

- post transcriptional modification of mRNA for one AA: glutamine to arginine (Q to R) in the GluR2 subunit - low Ca2+ permeability

Question 32

What happens to the GLuR2R subunit in ALS?

Answer 32

- becomes unedited GluR2Q isoform - highly permeable to Ca2+

Question 33

WHat are EAATs? Where are EAAT1 and EAAT2 found? How does ALS affect EAATs?

Answer 33

- regulate levels of glutamate at the synapse - EAAT1 and EAAT2 in astrocytes - ALS triggers downregulation

Question 34

Describe how loss of EAATs (e.g. in ALS) leads to excitotoxicity.

Answer 34

- glutamate accumulates in the synapse - leads to high intracellular Ca+ - no Ca2+ binding proteins: calbindin and calmodulin

Question 35

Which protein family do TDP-43 and FUS belong to? What are their function?

Answer 35

- hnRNP protein family - regulate RNA metabolism - bind thousands of RNA

Question 36

What is a hallmark feature of ALS? What other pathologies does this feature indicate?

Answer 36

- TDP-43 - cytoplasmic inclusions of TDP-43 also feature FTD, PD, and AD

Question 37

What are the effects of TDP-43?

Answer 37

- transcriptional regulation - stress granules - alternative splicing - mRNA transport - nucleus-cytoplasm shuttling - microRNA processing

Question 38

What was the first identified genetic link between familial FTD and ALS?

Answer 38

c9orf72

Question 39

What do intronic expansions in c9orf72 do? What is the mechanism of C9orf72? What does inactivation of C9orf72 lead to? Where are the inclusions?

Answer 39

- 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