Lecture 2

Question 1

What other names is motor neuron disease known as?

Answer 1

Amyotrophic lateral sclerosis and Lou Gehrig’s Disease

Question 2

What effect does the disease have?

Answer 2

Progressive neurodegenerative disease that attacks the upper and lower motor neurons- leads to weakness, muscle wasting, increasing loss of mobility in the limbs, later difficulty with speech, swallowing and breathing.

Question 3

What are the sub-classifications?

Answer 3

ALS, Progressive Bulbar Palsy, Progressive Muscular Atrophy, Primary Lateral Sclerosis and Kennedy’s Disease (v. rare, 2 families)

Question 4

When does it arise?

Answer 4

Usually 40-70 years old, but can occur at any stage

Question 5

Discuss its epidemiology

Answer 5

Sex ratio of 1.2 males to 1 female

5-10% cases are familial all others are idiopathic

Question 6

What are the four regions of the spine?

Answer 6

Cervical, Thoracic, Lumbar and sacral

Question 7

Outline the path of the upper motor neurons

Answer 7

Start in prentral gyrus (motor cortex), travel through the posterior limb of the internal capsule and then down the spine through the pyramidal decussation, the lateral corticospinal tract and meet the lower motor neuron in the anterior horn

Question 8

Which neurons are effected by ALS?

Answer 8

Both the lower and upper motor neurons

Question 9

What is commonly used for diagnosing progressive bulbar palsy?

Answer 9

Loss of function of motor cortex to Pons and medulla oblangata region; leads to loss of complex facial movement and swallowing. Upper motor neuron ALS.

Question 10

What are the types of lower motor neuron?

Answer 10

Alpha motor neurons; contact and contract extrafusal muscle fibres (major skeletal muscle contraction). Cell bodies found in the grey matter of the ventral horn.
Beta motor neurons; Sensory and motor, innervate intrafusal muscles but send collaterals to extrafusal muscles
Gamma motor neurons; innervate intrafusal muscles, sensitivity to stretch

Question 11

What are the two types of muscle?

Answer 11

Type 1: slow twitch, can contract for long periods, e.g. for posture
Type 2: Fast twitch, fast fatigue

Question 12

What is a motor unit?

Answer 12

A motor neuron and its muscle

Question 13

Why are motor neurons mostly described as ipsilateral?

Answer 13

They project to the same side of the body as they sit on the spine

Question 14

What are the signs for upper motor neuron lesions?

Answer 14

Weakness, increased reflexes and increased tone

Question 15

What are the signs for lower motor neuron lesions?

Answer 15

Weakness, atrophy, fasiculations, decreased reflexes and decreased tone

Question 16

What tools can be used to measure the signs?

Answer 16

Electromyography measurements, nerve conductive velocity, MRI and babinski reflex

Question 17

What is the broad pathology?

Answer 17

Pre central gyrus atrophy, neuronal loss of cranial nuclei, degeneration of corticospinal tract and chromatolysis

Question 18

What is the cellular pathology?

Answer 18

Bunina’s bodies, ubiquitinated inclusions, inclusions and neurofilament inclusions

Question 19

What are the mutations seen in familial ALS?

Answer 19

SOD1 (15%), TARDBP and FUS (5%), VCP (1%), C90RF72 (40%) and PFN1 (2%)

Question 20

What is commonly effected by mutations seen in ALS?

Answer 20

Superoxide metabolism, RNA metabolism, endosome, proteosome, microtubule traffic, actin cytoskeleton and microtubules.

Question 21

What is the role of SOD1?

Answer 21

Superoxide dismutases, converts superoxide radicals to peroxide.

Question 22

Where is SOD1 found?

Answer 22

Periplasm of the mitochondria

Question 23

What type of mutations are seen in SOD1?

Answer 23

Mostly mis-sense mutations, but also some non-sense mutations.

Question 24

What is the effect of these mutations on SOD1?

Answer 24

Not loss of function; simply knocking out, or altering expression of, SOD1 in mice does not lead to ALS. Likely gain of function mutations; suggests an acquired toxicity (neomorph)

Question 25

What has mice models shown about SOD1-G93A?

Answer 25

SOD1-G93A still has antioxidant function. Electro-physiological dysfunction precedes motorneuronal loss, decreasing coordination and after weight loss followed by dying back of motor neurons and end- plates that have been vacated by the dying neurons are partially repopulated by sprouting from other more 'death resistant' motor neurons

Question 26

How did Fischer show the dying back of the neurons?

Answer 26

Labelled the pre synaptic and axon using green tag for neuro filaments and synaptic vesicles and labelled post synaptic using red tag on toxin that binds ACh. As the mice aged saw dying back of the neurons, in green, leaving only the post synaptic, red.

Question 27

How was it shown that death resistant neurons sprout to the vacated end plates?

Answer 27

Schaefer | Compensatory synapses, motor neurons grew to fill vacant end plates shown using same tags as by Fischer

Question 28

What are the possible mechanisms of toxicity for familial ALS (FALS) SOD1 mutations?

Answer 28

Excitotoxicity from mishandling of glutamate (in spine) Mutant SOD1 causes ER stress (Depletion of chaperones) Mutant SOD1 inhibits the proteosome (Block up with aggregates) Misfolded SOD1 damages mitochondria (So less calcium removal by mitochondria) Extracellular toxicity from aberrant secretion of mutant SOD1 Mutant SOD1 generates extracellular superoxide Mutant SOD1 causes axonal disorganisation and disrupted transport Microhaemorrhages of spinal capillaries due to mutant SOD1 (Loss of tight junctions)

Question 29

What affects could SOD1 have on the mitochondria?

Answer 29

Effect ATP production Stop protein import Effect calcium buffering Cause apoptosis

Question 30

Which other cell types has SOD1 been shown to effect?

Answer 30

Expression of dismutase active SOD1 mutant in Schwann cells slows down ALS progression. Expression in both microglia and astrocytes will accelerate disease progression Expression of SOD1 in muscle or endothelial has no effect

Question 31

How have mutations in axonal transport machinery been implicated in ALS?

Answer 31

Mutations in both dynactin, retrograde, and tubulin, anterograde, lead to FALS. Heterozygous mutations in dynein can rescue axon transport defects and extended lifespan of SOD1-FALS mice.

Question 32

How was TDP-43 shown to be important?

Answer 32

This RNA binding protein was found in neuronal plaques in sporadic and familial ALS, but not SOD1-FALS. Mutations in TDP-43 were identified in FALS patients. Patients did not need to have the TDP-43 mutations to have TDP-43 pathology.

Question 33

Where are the majority of TDP-43 mutations seen?

Answer 33

Majority of TDP-43 mutations like in glycine rich domain

Question 34

What is TDP-43 involved in?

Answer 34

``` miRNA bio-genesis mRNA splicing Promoter silencing RNA translocation mRNA stability Stress granules ```

Question 35

Why are stress granules formed? | What are they involved in?

Answer 35

To sequester RNA and RNA binding proteins that are not required Involved in autophagy, apoptosis, signalling and RNA decay.

Question 36

How can these stress granules become plaques?

Answer 36

The gel formed in stress granules become plaques under prolonged stress

Question 37

What are the current treatments for ALS?

Answer 37

Riluzole; reduces excitotoxicity, and only used to prolong life by 2-3 months