Lecture 4

Question 1

Symptoms of HD

Answer 1

Uncontrolled movements, emotional problems, and loss of thinking ability (cognition)

Question 2

Who discovered HD

Answer 2

George Huntington

Question 3

What did George Huntington describe HD as

Answer 3

Hereditary form of chorea

Question 4

Chorea

Answer 4

Dance-like movements

Question 5

Huntingtons “peculurarities”

Answer 5

1. Hereditary nature
2. Tendency toward insanity and suicide
3. Manifestation as a fatal disease in adult life

Question 6

Origin of HD chromosome

Answer 6

European origin

Question 7

Where is the highest prevalance of HD

Answer 7

Maracaibo region of Venezuela

Question 8

How many cases of HD in venezuela

Answer 8

700 per 100,000

Question 9

Mutations in __ gene cause HD

Answer 9

HTT

Question 10

HTT provides intiructions for making a protein called

Answer 10

Huntingtin

Question 11

Role of huntingtin

Answer 11

Unknown, thought to play a role in neurons in the brain

Question 12

Mutation of HTT involves __ repeat

Answer 12

CAG trinucleotide

Question 13

Normal CAG repetition

Answer 13

10-35 times

Question 14

CAG repetition in HD

Answer 14

36-120 times

Question 15

People with __-__ CAG repeats may not develop symptoms

Answer 15

36-39

Question 16

People with __ or more repeats of CAG almost always develop the disorder

Answer 16

40

Question 17

More repeats of CAG =

Answer 17

Earlier onset, faster progression, and more severe HD

Question 18

What amino acid does CAG code for

Answer 18

Glutamine

Question 19

Testing for amplifications in CAG

Answer 19

PCR and electrophoresis

Question 20

__% of patients with HD have an expanded allele with 36 or more CAG repeats

Answer 20

99%

Question 21

Type of inheritance of HD

Answer 21

Autosomal dominant (usually passed from one affected parent)

Question 22

What happens to the size of the CAG repeat as it is passed from one generation to the next

Answer 22

Increases

Question 23

Can you get HD if you dont have a parent with HD

Answer 23

Yes but it is rare

Question 24

What is it called when the amount of CAG repeats increases from one generation to another

Answer 24

Expansion

Question 25

A larger number of repeats is associated with earlier onset of signs and symptoms. This is called ___

Answer 25

Anticipation

Question 26

What does expanision of CAG segment lead to

Answer 26

Production of abnormally long version of the huntingtin protein

Question 27

What happens to the elongated huntingtin in the cell

Answer 27

Cut into smaller, toxic fragments that bind together and accumulate in neurons

Question 28

Name for aggreates of huntingtin

Answer 28

Inclusions

Question 29

Where do inclusions start accumulating

Answer 29

Dendrites and axons

Question 30

Where do inclusions move from the dendrites and axons

Answer 30

To the nucleus

Question 31

What happens to a neuron with inclusions

Answer 31

It will die

Question 32

Inheriting mutant huntingtin is a ___

Answer 32

Gain of negative function

Question 33

Mutant huntingtin can interfere with ___

Answer 33

Normal cellular processes
Activate cell death (apoptosis)
Induce excitotoxicity
Neurodegeneration

Question 34

Inheriting mutant huntingtin means loosing the function of ____

Answer 34

Normal huntingtin protein

Question 35

Normal huntingtin mechanisms

Answer 35

Binds to transcription factor called REST and prevents it from entering the nucleus

Question 36

Mutant huntingtin mechanisms

Answer 36

Fails to bind or has weaker binding to REST. So rest enters the cell and blocks transcription of BDNF

Question 37

BDNF function

Answer 37

Necessary for neuronal growth and survival

Question 38

Loss of BDNF

Answer 38

Leads to neuronal death

Question 39

Pathologic mechanisms by which mutant huntingtin can cause neuronal death

Answer 39

Excitotoxicity
mitochondrial dysfunction 
caspase activation 
apoptosis 
nuclear localization 
aggregation 
synaptic dysfunction 
autophagy 
transcriptional dysregulation 
proteasomal dysfunction 
calcium homeostasis