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Huntington's & basal ganglia (finished) Flashcards

1
Q

What sort of disease is Huntington’s?

A

Neurodegenerative

Autosomal dominant - complete penetrance

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2
Q

What is the prevalence of Huntington’s disease?

A

4-10 per 100,000

(But may be twice as common as previously thought)

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3
Q

When does Huntington’s disease onset?

A

Most commonly presents in mid-life

Peak onset 30-50 yrs

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4
Q

How does Huntington’s progress?

A

Slow progressive 20-30 years

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5
Q

What are the general symptoms of Huntington’s disease?

A

Cognitive, motor & psychiatric symptoms

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6
Q

What gene is Huntington’s disease (mutation) caused by?

A
  • Huntington gene (HTT) is located on short arm chr 4
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7
Q

What is the mutation that causes Huntington’s?

A
  • 5’ end CAG repeat repeat seq
  • Protein extended to poly glutamate tail
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8
Q

What are the expansion sizes of the Huntington gene causing disease vs normal?

A

Normal = 17-21

Disease range = >40

Reduced penetrance = 36 - 39

Intermediate allele = 27 - 35

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9
Q

What does the autosomal dominant inheritance of Huntington’s disease mean for family members?

A
  • Autosomal dominant = complete penetrance
  • Most individual have +ive family history
  • If parent has gene 50% chance of child having it
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10
Q

How is Huntington’s disease onset determined?

A
  • Onset determined by clinical clinical onset of major symptoms
  • Relationship between CAG repeat length & age of onset
  • Not predictive on individual basis
  • Other genes that modify onset & phenotype - estimated 50% of variability in onset
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11
Q

What chromosome is the Huntingtin gene found on?

A

Chromosome 4

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12
Q

What does the Huntingtin gene code for?

A

Huntingtin protein

It us ubiquitously expressed

It is essential for embryonic development

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13
Q

Where is the Huntingtin protein primarily found?

A

In the cytoplasm

Some reports of nuclear localisation

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14
Q

What is the Huntingtin gene involved in?

A
  • Intracellular transport
  • Intracellular signalling
  • Metabolism
  • Neurogenesis & formation of CNS
  • Synaptic activity
  • Transcription regulation
  • Anti-apoptotic
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15
Q

What is the aggregation process?

A
  • Monomer
  • Oligomers formation (possibly toxic)
  • Globular intermediates (likely toxic)
  • Profibrils (possibly toxic)
  • Amyloid like fibres - beta-sheets (??)
  • Aggregates or inclusions (Protective?)
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16
Q

Why is aggregation important in Huntington’s?

A

The Huntington gene mutation causes protein to form aggregates

Lumps of proteins aggregates found in affected patients

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17
Q

What are the 6 elements of cellular pathology in Huntington’s disease?

A

1 - Protein aggregation

2 - Mitochondrial dysfunction

3 - Disrupted calcium signalling

4 - Vesicle transport defects

5 - Reduced BDNF expression

6 - Abnormal protein-protein interactions

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18
Q

How does reduced BNDF contribute to Huntington’s?

A

Aggregates can’t be removed anymore as BDNF expression is reduced

BDNF is important for cell survival

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19
Q

How is mitochondria dysfunction caused in Huntington’s?

A

Mutant Huntington protein impairs mitochondria

= reduced energy production, further stressing the cell

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20
Q

How is disrupted calcium signalling caused & what does it lead to?

A

Cause = protein interferes w the calcium in the endoplasmic reticulum

Means = altered Ca2+ levels can trigger stress pathways & contribute to neuronal dysfunction

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21
Q

What is the effect of impaired vesicle transport in Huntington’s?

A

Mutant Huntington = disrupts transport of vesicles in neuron

Vesicles are essential for communication between cells = leads to impaired signalling

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22
Q

What are the overall effects of the mutant Huntington protein?

A

Toxic gain of function & loss of normal functions

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23
Q

How does the brain size change in Huntington’s disease?

A

There is a 10-20% reduction in brain weight

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24
Q

How do the brain areas change in Huntington’s disease?

A
  • Dec striatal (caudate nuc & putamen) volume & cell death
  • Dec cortical volume & cell death
  • Inc ventricle size
  • Proteins inclusions throughout brain
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25
In the caudate nucleus & putamen (striatum), what is affected first in HD?
Selective loss of GABAergic medium spiny neurones (MSN) Then MSN in this area are particularly susceptible
26
What are the 2 type of medium spiny neurons found in the striatum?
Enkephalin containing MNS Substance P containing MSN
27
Which pathway do each of these belong to? Enkephalin containing MNS Substance P containing MSN?
Enkephalin containing MNS = Indirect pathway Substance P containing MSN = direct pathway
28
In what order do GABAergic medium spiny neurons in the striatum die in HD?
The enkephalin containing MSN dies first (indirect pathway) Then the substance P containing MSN die second (direct pathway)
29
Which neurons in the striatum are spared?
(The MSN die in the stratum in HD) Cholinergic interneurons of the straitum are spared
30
What are the components of the Basal Ganglia?
- Caudate nucleus - Putamen - Globus pallidus (internal & external) - Subthalamic nucleus (STN) - Substantia nigra --> pars reticula (SNr) & pars compacta (SNc)
31
What are the 2 pathways in the Basal Ganglia?
- Indirect pathway - Direct pathway
32
Where do both of the pathways in the basal ganglia originate?
Cell bodies originate in the striatum
33
Which sort of DA receptors are on each pathway of the basal ganglia
Indirect = D2 receptors Direct = D1 receptors
34
Where do the terminals of each of the pathways of the basal ganglia release onto?
(Both cell bodies originate in the striatum) Indirect = terminals release GABA onto EXTERNAL Globus Pallidus Direct = terminal release GABA onto INTERNAL Globus Pallidus
35
What do both of the pathways of the basal ganglia release onto the globus pallidus?
GABA
36
What sort of receptors are the D1 & D2 DA recpetors?
D1 = excitatory D2 = inhibitory
37
What is the loop of the direct pathway?
1. Cerebral cortex sends glutamatergic (excitatory signals) to striatum (more specifically- the putamen) 2. Striatum- medium spiny neurons (MSN) receives signals- contain D1 receptors + release GABA 3. Globus pallidus internus + substantia nigra pars reticulata = reduces inhibitory output to thalamus 4. Thalamus - becomes more active and sends excitatory signals back to motor cortex 5. Motor cortex- facilitates voluntary movements
38
What is the loop of the indirect pathway?
1. Cerebral cortex- excitatory input which sends glutamatergic signals to striatum 2. Striatum- MSNs contain D2 receptors and GABA is released 3. GABA sent to globus pallidus externus = results in reduced inhibition 4. STN- reduction of inhibtion allows this to become more active = sends glutamatergic signals to .... 5. Globus pallidus internas and substantia nigra pars reticulata = excitatory input increases inhibitory output to thalamus 6. Thalamus = activity supressed 7. Motor cortex = reduced excitatory input = inhibit movement
39
Describe the role of dopamine in direct and indirect pathways of the basal ganglia
Direct- Dopamine released from substantia nigra pars compacta and binds to D1 receptors in striatum = enhancing activity of pathway + promoting movement Indirect pathway = SNc binds to D2 receptors in striatum = decreases activity of pathway = reduced inhibitory output to thalamus = more excitatory signals to motor cortex = promotes movement
40
Where do both he indirect & direct pathway meet?
At the Globus pallidus internal (inderect passes thru the GPe first)
41
Where in the basal ganglia is it decided if moment is created & why?
The globus pallidus internal (This is where both direct & indirect pathways meet)
42
What causes the over movement in Huntington's disease?
1 - MSNs on indirect pathway begin to degenerate 2 - GPe is not excited = less inhibition of thalamus 3 - More glutamate is released onto the cortex
43
Which pathway switches movement on?
Direct
44
Which pathway switches movement off?
Indirect
45
What is involved in the psychiatric symptoms of Huntington's?
The medio orbito-frontal cortex (Thru the basal ganglia circuitries)
46
What is involved in the cognitive symptoms of Huntington's disease?
The dorsolateral prefrontal cortex & lateral orbito frontal-cortex
47
What are the early motor signs of Huntington's?
- Abnormal eye movements - Inappropriate hand & toe movements - General restlessness
48
What are the midcourse motor symptoms of Huntington's?
- Onset of involuntary movements (chorea) - Hypertonic rigidity & dystonia (slow abnormal movements w inc muscle tone)
49
What are the late stage motor symptoms of Huntington's?
Impaired voluntary movements - Rigidity - Bradykinesia - Dystonia - Convulsions - Weight loss
50
How can the late stage motor symptoms of HD lead to death?
Death from: - Pneumonia - Choking - Chronic skin ulcers - Nutritional deficits
51
What happens if both pathways are lost?
DA initiating movement via the striatum can no longer initiate movement as there is a break in circuitry
52
How does the onset of the cognitive symptoms of HD vary from the motor symptoms?
They may precede the motor onset by a decade or more
53
What are the cognitive symptoms of HD?
Dysexecutive syndrome: - Attention deficits, difficulty switching attention from one task to another - Impaired insight & judgement - Forgetfulness - Language deficits
54
What test can be used to diagnose HD & why?
The Stroop test --> where the colour is written in a different colour to what it is In HD you see a lot of errors in this test
55
How does the onset of psychiatric symptoms vary from the onset of motor?
These, like cognitive, may precede motor symptoms by a decade or more They are also highly variable between patients
56
What are the features of the psychiatric symptoms of HD?
CORE: - Irritability - Apathy - Depression ALSO: - Anxiety - Disinhibition - Obsessive/compulsive LESS COMMON: - Hallucinations & delusions
57
What are the other significant symptoms of HD (not motor, cognitive or psychiatric)?
- Weight loss - Sleep disturbance - Muscle weakness
58
How does HD cause weight loss?
- Involuntary movements - Loss appetite & motivation - Dysphagia - Metabolic dysfunctionH
59
How does HD cause sleep disturbance?
- Circadian rhythm disturbance - Depression - Loss of routine - 'Break-through' involuntary movements - Caffeine intake
60
How does HD cause muscle weakness?
- Primary muscle involvement (inclusion, mitochondrial dysfunction) - Disuse atrophy - Nutritional deficiencies
61
How can HD be treated?
There are no disease modifying treatments atm INSTEAD chorea can be managed by some drugs
62
What are the drugs used to treat chorea (in HD)?
- Antipsychotic medication - such as olanzapine (DA antagonist) - Tetrabenazine (Depletes DA & other monamines) - Benzodiazepines - such as clonazepam (enhances GABA)
63
What do the drugs used to treat chorea target?
Reducing dopamine OR Enhancing GABA
64
Why does GABA & DA being a target for the drugs to treat chorea work?
* Dopamine antagonists = stop the DA acting on the direct pathway --> can revive the cells left in the indirect pathway * GABAergric = mimic function of GABA on the thalamus = inhibit output on the cerebral cortex
65
What are the current management techniques for the psychiatric symptoms of HD?
Mostly standard pharmacological agents Citalopram (SSRI) is useful for irritability
66
What are the current management techniques for the cognitive symptoms of HD?
No treatments
67
What are the current management techniques for the motor symptoms of HD?
- Speech therapy - assessment of dysphagia/advice - Dietician/PEG - Physiotherapy - Late stage disease = palliative care, PEG - Family support
68
Can HD be treated?
There are no disease-modifying treatments currently availble Break through steps made recently - some promising trials in gene therapy etc

Disease in the brain (22 decks)

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