Lecture 10: Huntington's Disease Flashcards
What is Huntington Disease (HD) and what causes it?
- a genetic, hereditary, progressive neurodegenerative disorder caused by a defect in a gene on the short arm of chromosome 4
- Caused by a dominant gene that codes for a large brain protein called huntingtin.
What is the epidemiology of HD?
- Males and females have equivalent risk of inheriting HD.
- Onset of symptoms usually occurs between the ages of 35 and 55.
- Juvenile HD accounts for ~10% of all HD cases.
How is HD an insidious disease?
HD is a particularly insidious disease because its symptoms do not usually appear until later adulthood; people pass on their genes before they know they have Huntington’s disease
What are the clinical symptoms of HD?
Symptoms may include:
- Abnormal movements (involuntary movements - hyperkinetic, dystonia, motor coordination) known as chorea (“dance”);
- Cognitive difficulties, including dementia, due to cognitive degeneration; in the later stages
- Emotional difficulties (e.g. depression, apathy, irritability, personality disorders); later stages
Eventually the motor and intellectual deterioration become so severe that sufferers are incapable of feeding themselves, controlling their bowels or recognizing their own children.
What are the early and late stage symptoms of HD?
– Early Stages:
Face, trunk and limbs move involuntarily and rapidly; occupy the most real estate
Not too noticeable, can be disguised by patient fairly easily.
– As disease progresses:
Muscles begin to contract briefly and rapidly;
Arms and other body parts suddenly jerk;
Movements become uncoordinated, and eventually the whole body is affected.
– Later stages:
Cognitive difficulties; dementia, impulse control issues
Emotional difficulties; Changes in interests, Severe depression, apathy, excitability
Death usually occurs 13 to 15 years post onset of symptoms
What is the striatum made up of?
Striatum contains groups of specialized neurons called medium spiny neurons (MSN). (Also contains GABA interneurons.)
- MSN are specialized GABAergic cells (inhibitory); they can still respond to GABA, but responding to GABA does not make it a GABAergic cell, using/releasing GABA does
- Represent ~95% of neurons in the human striatum;
There are two main types of MSN: either express D1 (aka direct MSN) or D2 (aka indirect MSN) receptors (some contain both)
- Direct (D1) MSN excite their output structures (e.g. thalamus) and promote associated behaviors;
- Indirect (D2) MSN inhibit output structures (e.g. thalamus) and associated behaviors.
when dopamine binds to D1 receptors, it turns the neurons on but when dopamine binds to D2 receptors it turns the neurons off
What is the normal process of the BG circuit?
Direct Pathway:
– driven by the D1 MSN and facilitates movement
– D1 MSN turn on when dopamine from the substantia nigra binds it (while D2 MSN turn off and don’t release GABA when dopamine binds to it)
– when these D1 MSN turn on, the fire an action potential and will release GABA onto the globus pallidus interna (GPi). The GPi normally inhibits the thalamus but when GABA is released it becomes inhibited so the GPi can no longer inhibit the thalamus, and thus the thalamus is on (the inhibitor is inhibited) so you get movement
if you stimulate the direct pathway you will get movement
Indirect Pathway:
- driven by the D2 MSN and inhibits movement
- the striatum normally inhibits the GPe. When dopamine released from the substantia nigra binds to the D2 MSN in the striatum, it inhibits the striatum meaning the striatum can’t inhibit the Gpe so the Gpe is turned on and it inhibits the subthalamic nucleus. The subthalamic nucleus can’t turn on the Gpi so the Gpi cannot inhibit the thalamus. The thalamus is on and it turns on the motor cortex so you get movement
What’s the difference between the direct and indirect pathway of the BG circuit?
– the indirect pathway works to inhibit movement and the direct pathway works to facilitate movement.
Turning ____ the indirect pathway leads to movement
off
Turning ____ the direct pathway leads to movement
on
What is the pathology of Huntington’s Disease?
- Damage to neurons in the basal ganglia (i.e. D2 MSN) leads to loss of its inhibitory output to the thalamus which results in hyperkinesia
- Up to 95% loss of D2 medium spiny (GABA) neurons can be seen in later stages of the HD
- Typically, caudate, putamen (dorsal striatum) and Globus Pallidus are most affected
- However, as disease progresses, other areas of the brain are also affected (e.g. cerebral cortex shrinking & thinning).
What are the primary neurotransmitters in the BG?
- The primary neurotransmitters in the basal ganglia are GABA and Acetylcholine (Ach).
- These neurotransmitters normally act on the excitatory dopaminergic neurons in the nigrostriatal tract that extend from the substantia nigra to the basal ganglia to inhibit involuntary movements.
What happens to the BG in HD?
– in huntingtons, the direct pathway does not change at all. The D2 MSN are drivers of the indirect pathway that function to inhibit movement (when there’s no dopamine). When these D2 MSN die, they can’t inhibit (release GABA) to inhibit movement. Therefore, the indirect pathway is not functioning to inhibit movement but the direct pathway is always on creating movement.
– In the absence of dopamine, D2 MSN produce GABA and the indirect pathway is on and inhibiting movement. In Huntington’s, the D2 MSN are dead and not producing GABA so the indirect pathway is not working and there is movement. Therefore, the indirect pathway is turned off NOT because dopamine is released (and thus inhibiting the D2 MSN) it is directly because the D2 MSN are not functioning to produce GABA so the indirect pathway is not functioning
– the indirect pathway is always off and not inhibiting movement so you get hyperkinesia
What happens to the BG in PD?
in parkinsons, theres no dopamine so what you have is a direct pathway that can’t be turned on and an indirect pathway that can’t be turned off. That indirect pathway is stick in that on position and so you don’t get movement
What causes Huntington’s Disease?
- a mutation in the dominant huntingtin (HTT) gene that produces the huntingtin protein
- The mutated huntingtin gene contains an expanded CAG repeat coding for polyglutamine in the huntingtin protein.
- CAG is a codon that codes for the amino acid glutamine. Glutamine is very “sticky”.
- in Huntington’s disease, you have a massive expansion of CAG which codes for polyglutamine (poly meaning many, so many glutamines). Because of this, you have many glutamine amino acids in the huntingtin protein. Since glutamine is very sticky, too much of it making up the Huntingtin protein causes these huntingtin proteins to stick together and form aggregates. This happens right in and around the nucleus (intra or peri nuclear).
- any protein that has glutamine will be attracted to this clump of the huntingtin protein so you get a heterogenous mixture of a bunch of proteins in this clump
- CAG repeat lengths between 10-25 are normal. In HD patients we see CAG repeats above 36X so you get glutamine being transcribed 36 times back-to-back when creating the Huntingtin protein, making the protein ‘sticky’
- a positive correlation between CAG expansion and speed at which the disease progresses and the severity of the symptoms
- HD patients show misfolded huntingtin proteins that aggregate (i.e. clump) together, particularly in the dorsal striatum –> D2 MSN (because D2 MSN neurons use the huntingtin gene the most)
