Lecture 16: ALS and SMA

Question 1

Amyotrophic Lateral Sclerosis

Answer 1

a fatal neurological disease that attacks the nerve cells that control voluntary muscles. (both upper and lower motor neurons degenerate)

Question 2

Where are the upper motor neurons located?

Answer 2

primary motor cortex

Question 3

Where are lower motor neurons located?

Answer 3

brainstem or spinal cord

Question 4

What does degeneration of motor neurons lead to?

Answer 4

atrophy of the muscles

Question 5

Voluntary movement progressively lost as ___

Answer 5

motor neurons stop sending messages to the muscles

Question 6

How long do ALS patients usually live for?

Answer 6

A couple of years.
(with the exception of Steven Hawking)

Question 7

Symptoms of ALS

Answer 7

-muscle weakness in one or more: hands, arms, legs or muscle of speech, swallowing or breathing.
-twitching and cramping of muscles
-impairment of the use of the arms and legs
-“thick speech” and difficulty in projecting voice

Question 8

Advanced symptoms of ALS

Answer 8

-shortness of breath
-difficulty breathing and swallowing
-reliance on a ventilator

Question 9

Who gets ALS?

Answer 9

-people 35-70 years; can also develop during teenage or twenties
-risk of 1 in 1000 (rare but not rare)
-60% are men
-93% are Caucasian
-10% of people with ALS have another affected family member

Question 10

Why do motor neurons selectively degenerate in ALS?

Answer 10

-motor neurons are larger
-larger sizes require greater metabolic production: more mitochondria, increased oxidative stress, increased need for growth factors
-selective uptake- unique receptors on motor neurons may allow specific uptake of some toxins

Question 11

Is there a genetic cause behind ALS?

Answer 11

Yes, but…
-10% inherited (familial)
-sporadic (90% ALS cases are random)

Question 12

Risk factors for ALS?

Answer 12

-environmental factors ( dietary neurotoxin, extensive physical activity, pesticides and agricultural chemicals, industrial chemicals)
-genetic factors
-aging

Question 13

How can stem cells be used to treat or study ALS?

Answer 13

-replace lost motor neurons (very difficult)
-protect or repair effected endogenous motor neurons
-model the disease: iPSCs

Question 14

Potential solution for ALS

Answer 14

combining growth factor and stem cell therapy for ALS

Question 15

Spinal muscular atrophy (SMA)

Answer 15

a fatal neurological disease that attacks the nerve cells that control voluntary muscles
(only lower motor neurons degenerate)

Question 16

SMA facts

Answer 16

-autosomal recessive motor neuron disease
-1 in 6000 people suffer from SMA
-SMA is caused by progressive degeneration of motor neurons in the spinal cord and brainstem
-causes progressive weakness and wasting of the voluntary muscles
-SMA is caused by mutations or deletions in the gene SMN

Question 17

What is the primary cause of SMA?

Answer 17

The disease is caused by the loss or conversion of SMN1 but varying levels of SMN2 can partially compensate.

Question 18

How many kinds of SMA are there?

Answer 18

3
Type I, II, and III

Question 19

How do we model SMA?

Answer 19

modeling SMA by deleting one or two copies of the mouse SMN gene

Question 20

Which SMA is the most severe?

Answer 20

Type I SMA is the most severe because it makes the least amount of protein

Question 21

What is spinraza?

Answer 21

Spinraza is an antisense oligonucleotide that binds to part of the SMN2 gene and increases the production of SMN2 mRNA and protein, thereby compensating for the loss of SMN1

Question 22

SMA fibroblasts and iPSC produce decreased ___

Answer 22

SMN mRNA

Question 23

When SMA iPSCs are differentiated into motor neurons what happens?

Answer 23

Less survive and surviving MNs are smaller.

Question 24

Can these cells (SMA iPSCs) be used to identify drugs that might help treat SMA?

Answer 24

SMA iPScs have fewer nuclear “gems” containing SNM protein. Treatment with HDAC inhibitors that increase transcription partially restore SNM levels.

Question 25

Can a similar approach be used for ALS?

Answer 25

Antisense oligonucleotides can also be used to target and break down specific mRNAs and prevent their translation to proteins.

Question 26

What are the conclusions to this lecture?

Answer 26

Both stem cells transplantation and iPSC disease modeling studies are being used to discover new treatments for motor neuron disease such as ALS and SMA
Because these disorders are rare, there is less funding for them than many other more common diseases.
However, some of the earliest clinical studies of stem cell transplantation and antisense oligonucleotide therapies are being pursued in these patients.

Question 27

Why is the FDA more willing to take risks with severe/rare diseases?

Answer 27

Because rare diseases are very severe and fatal vs other diseases have a slow decline.
People with rare diseases get more new approaches/riskier attempts at treating their illness because the patients have no other options.