Huntington's Genetics and Biochemistry

Question 1

What is the genetic cause of Huntington’s disease?

Answer 1

a CAG trinucleotide repeat

causes an abnormally long Huntingtin protein

Question 2

What is the inheritance pattern for HD?

Answer 2

autosomal dominant disorder - children of affected parents have 25%

Question 3

Who sequenced the Hunginton gene? WHere?

Answer 3

Nancy Wexler in Lake Maracaibo Venezuela

Question 4

True or false,

Like AD, HD stems form multiple genetic causes.

Answer 4

false - only ONE cause…in every single patient

Question 5

What is the prevalence of HD? Who gets it most often?

Answer 5

1/10,000 or northern european background

much less prevalent in Asian and African populations

no gender variation

age of onset 35-50, but ranges from 2-85

Question 6

What is the life expectancy after an HD diagnosis and what are the typical causes of death?

Answer 6

15-20 years

aspiration pneumonia, heart disease, falls, suicide, violence

Question 7

Where in the brain is Htt expressed?

Answer 7

it’s widespread in peripheral tissues, and in th ebrain it’s expressed in neurons - essential for development, but we don’t really know it’s function yet

Question 8

Where in the brain are neurons most affected by mutant Htt?

Answer 8

the striatum

Question 9

How did they map the geme?

Answer 9

recombination frequency family linkage mapping

Question 10

What does the CAG repeat encode for?

Answer 10

glutamine (Q)

(which is why it’s a polyQ tract)

Question 11

What is the likely cause of the CAG repeat?

Answer 11

not fully known, but likely involves defects in DNA replication fidelity – initially in the germ line, but then in somatic cells as disease progresses

Question 12

What is the normal number of polyQs? At what number do you start to see HD and at what number do you have 100% penetrance?

Answer 12

less than 35 is normal

36-41 has incomplete penetrance

40-60 polyQ repeats gives you 100% penetrance

over 60 gives you juvenile onset HD

Question 13

What is anticipation and how does it relate to HD?

Answer 13

In genetics, anticipaiton is when the age of onset tends to decrease in successive generations

this is definitely the case in HD, where children almost always have onset of symptoms earlier than their parents - sometimes even BEFORE their parents present!

Question 14

Is anticipaiton more likely when inheritance is from a maternal or paternal acarrier? Why?

Answer 14

paternal

they make sperm their whole lives, so there is a greater mutation risk in their germ line

Question 15

Besides anticipation and # of CAG repeats, what can influence age of onset and severity of symptoms in HD?

Answer 15

Modifier genes (affects about 30-40% of the disease)

polymorphisms in GluR6, ApoE4 is protective while ApoE2/3 genotype decreases age of onset in males, variants in NMDA receptor, SNP in the PGC1-alpha gene

Question 16

What environmental factors hav ebeen found to affect HD (and other neurodegenerative diseases)?

Answer 16

omega3 oils are protective while omega6 oils increases susceptibility

environmentla enrichment slows disease progression

Question 17

How many neurodegenerative diseases have been ofund to be due to expanded polyQ tracts so far? Inheritance?

Answer 17

9

all autosomal dominant except Kennedy’s disease which is x-linked recessive

Question 18

What is the pathogenesis for HD (and the other polyQ diseases)?

Answer 18

you get an abnormally lengthed protein which undergoes proteolytic cleavage

specifically from exon 1 of the Htt gene, you get an increased rate of cleavage at a nearby site, resulting in the release of a toxic fragment

while the wildtype fragment would noramlly get degraded in the cytoplasm, this one doesn’t

they enter the nucleus of neurons and accumulate as protein aggregates

Question 19

What are the protien aggregates in the nucleus called?

Answer 19

nuclear inclusions

Question 20

What do the nuclear inclusions do?

Answer 20

they form basket-like structures that trap other proteins, especially trasncription factors and wildtype Htt

Question 21

Where in the brain do NI occur? Before or after clinical symptoms?

Answer 21

striatum and cortex

before clinical symptoms

Question 22

What is the controversy around the NI?

Answer 22

some studies suggest they’re actually neuroprotective and may protect against cell death - that smaller soluble aggregates are the source fo the dysfunction

Question 23

What are the 6 major cellular defects associated with HD?

Answer 23

1. dysregulation of transcription
2. altered neurotransmitters
3. excitotoxicity
4. interference with wildtype Htt - changes in axonal transport and synaptic fucntion
5. apoptosis
6. oxidative stress from mitochodnrail dysfunction

Question 24

Why does haploinsufficiency NOT explain the HD phenotype?

Answer 24

humans that are heterozygous at the Htt develop no pathology

mice that express an expanded CAG repeat fragment in addition to two wildtype copies of Htt do develop HD

Question 25

What symptoms come first in HD?

Answer 25

the psychiatric symptoms of depression, irritability, impulsiveness and aggression

may precede motor onset and cell death by as much as 20 years!

Question 26

What is a major target for the dysregulation of transcription in HD and what is the effect?

Answer 26

CBP - a histone acetyltransferase

this means you don’t get acetylation of the DNA, so it doesn’t open up for transcription and you don’t get transcription of necessary genes like the D2 receptor gene

(you also get trapping of transcription factors in the baskets)

Question 27

What NT is deficiency in HD?

Answer 27

GABA - because of a loss of spiny neurons in the basal ganglia

Question 28

Upregulation of what receptors in HD causes excitotoxicity associated with chronic exposure to excitatory AA like glutamine and glutamate?

Answer 28

NMDA receptors

Question 29

What are basically the 5 points along the corticostriatal pathway where dysfunction may contribute to excitotoxicity?

Answer 29

1. increased glutamate release
2. reduced uptake of glutamate by glia
3. hypersensitivity of the NMDA receptors
4. altered intracellular ca2+ homeostasis
5. mitochondrial dysfunction

Question 30

How does mitochondrial dysfunction lead to cell death>

Answer 30

you get release of cytochrome C leading to caspase activation and cell death

Question 31

What is a target of Htt that is a key regulator of mitochodnrail biogenesis and respiration?

Answer 31

PGC-1alpha