Dr. Bennett Part 2

Question 1

SPINAL MUSCULAR ATROPHY (SMA). What is the basic problem

Why is SMN important? If there is no SMN, what happens?

Answer 1

It’s a genetic disease (autosomal recessive)

You are missing or have a broken SMN1 gene
This gene makes SMN protein

SMN protein is needed for:
motor neuron survival

SMN1 needed for development of motoneurons

no protein = motoneurons die in ventral horn = atrophy

Question 2

What goes wrong in SMA?

What happens to muscles

Answer 2

SMN1 doesn’t work → ↓ SMN protein
Motor neurons die (in spinal cord)

👉 Specifically:
in the ventral horn

Muscles:
No motor neurons → no signal to muscles
→ muscles waste away (atrophy)

Question 3

Symptoms of SMA?

Diagnosis of SMA based on:

Answer 3

Weak muscles
Trouble breathing 😮‍💨
Difficulty sitting/walking
Scoliosis
Swallowing problems
Weak sucking reflex (in babies)

Whole body muscle weakness

Diagnosis: 5 symptoms
poor muscle tone in limbs and trunk
feeble movements of arms and legs
difficulty swallowing
weak sucking reflex
impaired breathing

Question 4

Most common genetic cause of infant death is what?

Answer 4

SMA

Question 5

What are the 4 severity types of SMA? (lifespan?)

Answer 5

Type I (most severe) (Werdnig-Hoffman disease)
Starts before 6 months
Cannot: sit, crawl, walk
Severe breathing problems
60% of all SMA patients
Lifespan: ~2–3 years

Type II
Starts before 18 months
Can sit ✅
Cannot walk ❌
Can live into adulthood

Type III (Kugelberg-Welander disease or Juvenile Spinal Muscular Atrophy)
symptoms appear between 18 months and early adulthood
Can walk but weak
Frequent respiratory infections
Normal lifespan

Type IV (mildest)
Adult onset (>35)
Mild walking problems

Question 6

What is the important extra gene related to SMA?

Answer 6

SMN2

BUT:
it usually makes a short, nonfunctional protein (SMN)

Idea: More SMN2 copies = less severe disease

Question 7

What is the treatment for SMA?

Answer 7

Nusinersen (VERY IMPORTANT)
This is an antisense oligonucleotide

It fixes how SMN2 mRNA is spliced
→ makes full-length (working) SMN protein

Compensates for missing SMN1

Can dramatically improve / even “functionally cure” disease

Gene therapy
Uses viruses to deliver a working SMN1 gene
👉 Result:
body can now make SMN protein again

Question 8

What is the animal model for SMA?

Answer 8

Mice with SMA:
smaller
weak
can’t support weight

👉 used to study disease

Question 9

What is the basic problem associated with Duchenne Muscular Dystrophy (DMD)

Answer 9

It’s a genetic muscle disease

Mutation in the dystrophin gene
Gene is on the X chromosome

Question 10

What does dystrophin normally do? (related to DMD)

What goes wrong?

Answer 10

Think of dystrophin as a shock absorber / anchor

It connects:
inside of muscle cell (contractile machinery)
to outside (extracellular matrix)

👉 So:
It keeps muscle cells stable during contraction

No dystrophin → muscle cells are fragile
When muscles contract:
→ cells get damaged

👉 Over time:
damage builds up
muscle cells die
replaced with fat

result: Muscle wasting (atrophy)

Question 11

What are symptoms of DMD? (classic sign and progression)

When death?

Detected with 95% accuracy by genetic studies performed during

Answer 11

Starts early:
Around age 3
Child:
doesn’t run well
has weak legs
Progression:
Weakness starts in legs first
Gets worse quickly
Classic sign:
Pseudohypertrophy (BIG calves)

👉 BUT:
looks big because of fat, not muscle
Later:
Wheelchair by ~age 12
Death in 20s–30s

Detection: pregnancy

Question 12

Genetics related to DMD?

Answer 12

X-linked → mostly affects boys
Very large gene → high chance of mutation

Question 13

When can DMD be detected?

Answer 13

Can be detected before birth
~95% accuracy with genetic testing

Question 14

Treatment for DMD?

Answer 14

Currently: No cure

Future idea:
Gene therapy using viral vectors
→ deliver correct dystrophin gene

Question 15

For a long time, there was little functional recovery after spinal cord injury, no regen, no treatment,. We know that injury location determine deficits, and that injury involves motor and sensory functions controlled by spinal cord. SCI mainly occurs to who and because of what?

Answer 15

accidents, male under 30 (recreation, cars, motorbike)

Question 16

Lesion involves motor, sensory and autonomic function. Thus common problems include:

What is Autonomic dysreflexia

Answer 16

Paralysis (can’t move)
Muscle spasms (later)
Loss of sensation
Neuropathic pain (nerve pain)
Autonomic dysreflexia (dangerous BP changes)
Loss of bladder control

Question 17

What are the types of injuries (mostly indirect)

Answer 17

Compression (squeezing)
Contusion (bruising)
Laceration (tearing)
Stretching

OR

Direct trauma (e.g., gunshot)

Question 18

Anatomical complete vs physiological complete injury

Answer 18

Anatomical complete = looks fully damaged structurally

Physiological complete = no function (even if structure partly intact)

Question 19

Paralysis types: paraplegia vs tetraplegia (include location of SC injury and severity)

Answer 19

Lower spinal cord injury (less severe)
👉 Paraplegia
legs affected

Higher spinal cord injury (more severe)
👉 Tetraplegia (quadriplegia)
arms + legs affected

Question 20

Santiago Ramón y Cajal discovered what?

Answer 20

neurons don’t regenerate well in CNS

Question 21

After injury, axons try to regrow. They form a growth cone (like a searching tip), but when growth fails:

Answer 21

forms retraction bulbs
👉 means: aborted (failed) regrowth

Question 22

What is the timeline of SCI

Answer 22

primary injury (immediate)
actual trauma. axons get cut, crushed, damaged. Happens to gray matter and white matter

spinal shock (early phase)
everything below injury shuts down temporarily. less of descending signals from brain, neurons can’t maintain normal function. Then, membrane potentials break down, more Ca enters cell, decrease in blood flow, oxygen and nutrients, ATP, neuromodulators like 5-HT
No activity → paralysis + no reflexes

secondary injury (days-weeks)
Ischemia (low blood flow)
Inflammation + swelling (edema)
Glutamate toxicity → Ca²⁺ overload
BBB breakdown
Immune invasion:
macrophages
cytokines
microglia and astrocytes activated
free radicals (ROS) cause more cell death
Damage spreads beyond original injury

Scar formation (weeks)
forms a glial scar made of astrocytes (outer boundary) and pericytes (inner core)
contains damage but also blocks regeneration (collapse of growth cones from proteoglycans and myelin (Nogo)
Inflam (Sarm1) promote axon Wallerian degen (in distal axon beyond cut), but not complete (myelin debris)

neuronal plasticity

long term injury

Question 23

What is the blood flow problem that results from pericytes during scar formation?

What does the damaged area look like?

Answer 23

Pericytes cause long-term damage

Injury → low oxygen (hypoxia)
Pericytes:
contract (like rigor mortis)
cause vasoconstriction

Then,
surviving pericytes:
make amines (via AADC)
→ keep vessels constricted

Chronic low blood flow (hypoxia) = ongoing damage

You get:
Severed axons
Demyelinated axons
Failed signal transmission

Also:
Old bleeding (hemorrhage)
Dead cells (apoptosis)
Invading macrophages
Scar tissue
Inhibitory molecules (proteoglycans)

Question 24

Long-term injury (chronic phase)/. Damage continues over time. What are the key players?

What happens?

Answer 24

Pericytes
Neurons
Astrocytes
Microglia
Oligodendrocytes

1) chronic hypoxia = due to pericytes

2) chronic inflammation = microglia stay active

3) excess neuronal activity. due to inflammation, ↓ ADAR2 → abnormal signaling leads to spasms and pain

4) plasticity. Neurons try to adapt by sprouting or pruning. This can help OR worsen function

5) permanent scar: blocks regen forever

6) demyelination: worsens signal transmission

Question 25

What did Albert Aguayo ask?

Answer 25

attempted to find a treatment for SCI asked a simple question Why can nerves regrow in the body (PNS), but not in the spinal cord (CNS)?

Question 26

Why DOES the PNS regenerate in SCI?

Answer 26

Peripheral nerves (like in your arms/legs) can regrow because of 3 things: 1) permissive environment Schwann cells clean up myelin debris and release growth factors. environment says grow! 2) good intrinsic growth ability neurons activate growth proteins: GAP-43. neurons are ready to regrow 3) no scar barrier. no strong inhibitory scar like in CNS PNS = supportive environment → regeneration works

Question 27

Why DOESNT the CNS regenerate in SCI?

Answer 27

Martin E. Schwab found that CNS myelin contains inhibitory molecules like Nogo, MAG, OMgp, ephrins, which bind to NgR (Nogo receptor) This activates the Rho pathway, causing the growth cone to collapse. So axons try to grow, then instantly stop another problem: growth cone collapse and regrowth fails another problem: scar blocks growth CSPGs (chondroitin sulfate proteoglycans) are found in astrocyte scar and perineuronal net They block axon growth and plasticity (chemical stop signs)

Question 28

Aguayo’s BIG experiment. What did he test and what was the result? Can this be used for treatment?

Answer 28

What if we give CNS neurons a PNS environment? result: CNS axons can regrow in a PNS-like environment. AKA the problem is the environment, not the neuron itself Idea for treatment Use peripheral nerve grafts Or make CNS environment more like PNS

Question 29

What is electromyography (EMG)?

Answer 29

extracell recording of AP travelling down muscle fibers during muscle contractions EMG reflects motoneuron AP firing