Huntington's & basal ganglia (finished) Flashcards
What sort of disease is Huntington’s?
Neurodegenerative
Autosomal dominant - complete penetrance
What is the prevalence of Huntington’s disease?
4-10 per 100,000
(But may be twice as common as previously thought)
When does Huntington’s disease onset?
Most commonly presents in mid-life
Peak onset 30-50 yrs
How does Huntington’s progress?
Slow progressive 20-30 years
What are the general symptoms of Huntington’s disease?
Cognitive, motor & psychiatric symptoms
What gene is Huntington’s disease (mutation) caused by?
- Huntington gene (HTT) is located on short arm chr 4
What is the mutation that causes Huntington’s?
- 5’ end CAG repeat repeat seq
- Protein extended to poly glutamate tail
What are the expansion sizes of the Huntington gene causing disease vs normal?
Normal = 17-21
Disease range = >40
Reduced penetrance = 36 - 39
Intermediate allele = 27 - 35
What does the autosomal dominant inheritance of Huntington’s disease mean for family members?
- Autosomal dominant = complete penetrance
- Most individual have +ive family history
- If parent has gene 50% chance of child having it
How is Huntington’s disease onset determined?
- 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
What chromosome is the Huntingtin gene found on?
Chromosome 4
What does the Huntingtin gene code for?
Huntingtin protein
It us ubiquitously expressed
It is essential for embryonic development
Where is the Huntingtin protein primarily found?
In the cytoplasm
Some reports of nuclear localisation
What is the Huntingtin gene involved in?
- Intracellular transport
- Intracellular signalling
- Metabolism
- Neurogenesis & formation of CNS
- Synaptic activity
- Transcription regulation
- Anti-apoptotic
What is the aggregation process?
- Monomer
- Oligomers formation (possibly toxic)
- Globular intermediates (likely toxic)
- Profibrils (possibly toxic)
- Amyloid like fibres - beta-sheets (??)
- Aggregates or inclusions (Protective?)
Why is aggregation important in Huntington’s?
The Huntington gene mutation causes protein to form aggregates
Lumps of proteins aggregates found in affected patients
What are the 6 elements of cellular pathology in Huntington’s disease?
1 - Protein aggregation
2 - Mitochondrial dysfunction
3 - Disrupted calcium signalling
4 - Vesicle transport defects
5 - Reduced BDNF expression
6 - Abnormal protein-protein interactions
How does reduced BNDF contribute to Huntington’s?
Aggregates can’t be removed anymore as BDNF expression is reduced
BDNF is important for cell survival
How is mitochondria dysfunction caused in Huntington’s?
Mutant Huntington protein impairs mitochondria
= reduced energy production, further stressing the cell
How is disrupted calcium signalling caused & what does it lead to?
Cause = protein interferes w the calcium in the endoplasmic reticulum
Means = altered Ca2+ levels can trigger stress pathways & contribute to neuronal dysfunction
What is the effect of impaired vesicle transport in Huntington’s?
Mutant Huntington = disrupts transport of vesicles in neuron
Vesicles are essential for communication between cells = leads to impaired signalling
What are the overall effects of the mutant Huntington protein?
Toxic gain of function & loss of normal functions
How does the brain size change in Huntington’s disease?
There is a 10-20% reduction in brain weight
How do the brain areas change in Huntington’s disease?
- Dec striatal (caudate nuc & putamen) volume & cell death
- Dec cortical volume & cell death
- Inc ventricle size
- Proteins inclusions throughout brain
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
What are the 2 type of medium spiny neurons found in the striatum?
Enkephalin containing MNS
Substance P containing MSN
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
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)
Which neurons in the striatum are spared?
(The MSN die in the stratum in HD)
Cholinergic interneurons of the straitum are spared
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)
What are the 2 pathways in the Basal Ganglia?
- Indirect pathway
- Direct pathway
Where do both of the pathways in the basal ganglia originate?
Cell bodies originate in the striatum
Which sort of DA receptors are on each pathway of the basal ganglia
Indirect = D2 receptors
Direct = D1 receptors
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
What do both of the pathways of the basal ganglia release onto the globus pallidus?
GABA
What sort of receptors are the D1 & D2 DA recpetors?
D1 = excitatory
D2 = inhibitory
What is the loop of the direct pathway?
- Cerebral cortex sends glutamatergic (excitatory signals) to striatum (more specifically- the putamen)
- Striatum- medium spiny neurons (MSN) receives signals- contain D1 receptors + release GABA
- Globus pallidus internus + substantia nigra pars reticulata = reduces inhibitory output to thalamus
- Thalamus - becomes more active and sends excitatory signals back to motor cortex
- Motor cortex- facilitates voluntary movements
What is the loop of the indirect pathway?
- Cerebral cortex- excitatory input which sends glutamatergic signals to striatum
- Striatum- MSNs contain D2 receptors and GABA is released
- GABA sent to globus pallidus externus = results in reduced inhibition
- STN- reduction of inhibtion allows this to become more active = sends glutamatergic signals to ….
- Globus pallidus internas and substantia nigra pars reticulata = excitatory input increases inhibitory output to thalamus
- Thalamus = activity supressed
- Motor cortex = reduced excitatory input = inhibit movement
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
Where do both he indirect & direct pathway meet?
At the Globus pallidus internal
(inderect passes thru the GPe first)
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)
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
Which pathway switches movement on?
Direct
Which pathway switches movement off?
Indirect
What is involved in the psychiatric symptoms of Huntington’s?
The medio orbito-frontal cortex
(Thru the basal ganglia circuitries)
What is involved in the cognitive symptoms of Huntington’s disease?
The dorsolateral prefrontal cortex & lateral orbito frontal-cortex
What are the early motor signs of Huntington’s?
- Abnormal eye movements
- Inappropriate hand & toe movements
- General restlessness
What are the midcourse motor symptoms of Huntington’s?
- Onset of involuntary movements (chorea)
- Hypertonic rigidity & dystonia (slow abnormal movements w inc muscle tone)
What are the late stage motor symptoms of Huntington’s?
Impaired voluntary movements
- Rigidity
- Bradykinesia
- Dystonia
- Convulsions
- Weight loss
How can the late stage motor symptoms of HD lead to death?
Death from:
- Pneumonia
- Choking
- Chronic skin ulcers
- Nutritional deficits
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
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
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
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
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
What are the features of the psychiatric symptoms of HD?
CORE:
- Irritability
- Apathy
- Depression
ALSO:
- Anxiety
- Disinhibition
- Obsessive/compulsive
LESS COMMON:
- Hallucinations & delusions
What are the other significant symptoms of HD (not motor, cognitive or psychiatric)?
- Weight loss
- Sleep disturbance
- Muscle weakness
How does HD cause weight loss?
- Involuntary movements
- Loss appetite & motivation
- Dysphagia
- Metabolic dysfunctionH
How does HD cause sleep disturbance?
- Circadian rhythm disturbance
- Depression
- Loss of routine
- ‘Break-through’ involuntary movements
- Caffeine intake
How does HD cause muscle weakness?
- Primary muscle involvement (inclusion, mitochondrial dysfunction)
- Disuse atrophy
- Nutritional deficiencies
How can HD be treated?
There are no disease modifying treatments atm
INSTEAD chorea can be managed by some drugs
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)
What do the drugs used to treat chorea target?
Reducing dopamine
OR
Enhancing GABA
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
What are the current management techniques for the psychiatric symptoms of HD?
Mostly standard pharmacological agents
Citalopram (SSRI) is useful for irritability
What are the current management techniques for the cognitive symptoms of HD?
No treatments
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
Can HD be treated?
There are no disease-modifying treatments currently availble
Break through steps made recently - some promising trials in gene therapy etc
