Huntington’s disease
Autosomal-dominant neurodegenerative disease that has a 50% chance of being inherited. 1/10 000 affected (both
genders equally).
Specifically affects the medium spiny neurons in the striatum. Atrophy of the striatum and enlargement of ventricles
No current ‘cure’ - Fatality 10-15 years after clinical diagnosis.
Genetics
Caused by one gene – repeats of CAG. It is normal to have 7, more than 35 repeats is possible HD. Spermatogenesis
can contribute to increase in CAG which is passed to children. As CAG repeats increases, the age of onset lowers.
Diagnosis and symptoms
Genetic diagnosis is the presence of CAG repeats.
Clinical diagnosis is done using the UHDRS (Unified HD ranking scale):
- Motor symptoms: Chorea, Akinesia (problems initiating movement), Bradykinesia (slowness), Altered
gait, Subtle motor abnormalities.
- Cognitive symptoms: Cognitive decline. Perseverance. Reversal learning problems. Memory. Difficulties
calculating risk – can lead to gambling and addiction problems. Facial recognition. Emotional recognition
- Psychiatric symptoms: Depression. Mania. Apathy (not caring). Aggression. Suicidal thoughts. OCD.
Irritability
Juvenile HD: Happens at 20 years of age. 5-10% of cases of HD. Different clinical symptoms. Larger numbers
of CAG repeats.
Managing symptoms: Anti-chorea drugs. Anti-psychotics. Anti-depressants. Sleeping tablets. Anti-
spasticity.
Modelling HD
Models
Cellular models: Synthetically long CAG alleles – derived from patient fibroblasts. Human telomerase reverse
transcriptase used to immortalize the cells. Handy for initial drug screens but not representative of whole organisms.
Non-vertebrate models: Drosphila melanogaster - 60% genetic similarity to humans. Similar brain structure. Life span
of 50 days.
Vertebrate models: Mouse - 97.5% similar. Similar brain structure but no internal capsule. Life span of 2-3 years.
- Transgenic mouse is when the gene of interest is randomly integrated into the cell. The method is
quicker and has a higher throughput.
- Knock-in mouse is a specific integration that expands the CAG repeat. More representative of the
human model. Chimeric IT15 model contains human genes knocked into mouse gene. Insertion of CAG
contain mouse genes only.
Large vertebrate: Sheep/mini pig - Genetic & neuroanatomical similarities. Long life span of 10-20 years. Require
housing.
Primate – most similar to human brain but not usually used due to ethics. Only ever very small studies.
Behavioural tests
Motor tests: Rotor-rod and balance beam shows dexterity and gate. Grip strength. Gait analysis - look at footprints
Cognitive tests:
- Light test - mice put their nose in a hole when it lights up. Can test attention and reaction time.
- Marble burying - bury the marbles = more anxious
- Open and enclosed space – more time spent in enclosed area = more anxious
mHtt cleavage - if a long Huntington gene causes the disease, why not chop it down?
The N-terminal of normal Htt gene is very important in cellular processes. The protein that the Htt gene produces is
cleaved (split) and if it goes wrong it can cause disease. Cleavage of the Htt protein has to happen to maintain health
, Effects of mHtt: Alters endocytic and secretory pathways. Proteasomal function. Calcium handling and
mitochondrial function. Reduced transport of growth factors. Triggers apoptotic cascades, free radical production
and glutamate toxicity.
Can also lead to huntingtin inclusion formation where proteins clump in the cell and cause it die. Is this a bad thing?
Inclusions reduce the level of mutant hungtingtin
The cleaved N-terminal fragment may be more pathogenic than the full-length protein.
Inclusion physically blocks cellular machinery.
Inclusion may be formed from insufficient protein degradation.
The formation of inclusions may promote the degradation of toxic aggregates.
Overall, protects to some extent but then there comes a point where it becomes pathogenic.
R6/2 mouse models support the theory that it is the N-terminal fragment of the gene which is implicated specifically
in HD - these models have the truncated N-terminal form of the gene in their genome.
Exception: really long CAG repeats, above 335 = transgene protein that is too large for passive entry into the
nucleus via the nuclear pore.
Inclusions exist just in the cell, not in the nucleus, which results in a less severe phenotype.
Somatic expansion: When DNA repair goes wrong and repeating sections of DNA become unstable.
In regard to HD this means over your lifetime you can gain more CAG repeats - particularly high levels in the striatum
and cortex of brain. Somatic expansion usually associated with an earlier age of disease onset.
Potential therapies
Example treatments:
Pharmacological: Tetrabenazine.
Reduce hyperkinetic movement.
Promotes depletion of monoamine neurotransmitters (serotonin, norepinephrine, dopamine).
Weak binding affinity to D2 receptors
Side effects = increased risk of depression and suicidal thoughts - not good, HD already increases this risk
Non-pharmacological: exercise
Better fitness
Lower UHDRS (Unified Huntington's Disease Rating Scale) motor score
Lower weight – not good, weight loss is already a problem in HD
Potential treatments
1. Cell transplantation: replacing cells that are lost in HD, with WGEs from terminated foetuses or stem cells.
Only used in advanced cases of HD when there is no other options.
Moral and logistical issues, immunosuppression required, very invasive procedure (striatum).
Animal models create debate whether to use tissue pieces or cell suspension.
Variation in surgical technique in different parts of the world.
Results: small improvements in motor function and cognition – not enough studies
Positive case study: a decade after transplantation, the transplanted grafts were identified. It
showed that the HD cells had not overgrown/“infected” the graft cells.
Negative case study: Patient received 10 transplants - developed worsening asymmetric upper
motor neuron symptoms + progression of Huntington’s disease. He died 10 years after
transplantation and his brain showed huge overgrowth and cysts without evidence to suggest graft
rejection or HD pathology.
2. Pridopidine: Study done that suggested this drug demonstrated slowing of progression of Huntington
disease in HD patients, as measured by Total functional capacity.
Unusually high placebo effect.
Ultimately, study was dismissed due to not enough appropriate evidence.
Autosomal-dominant neurodegenerative disease that has a 50% chance of being inherited. 1/10 000 affected (both
genders equally).
Specifically affects the medium spiny neurons in the striatum. Atrophy of the striatum and enlargement of ventricles
No current ‘cure’ - Fatality 10-15 years after clinical diagnosis.
Genetics
Caused by one gene – repeats of CAG. It is normal to have 7, more than 35 repeats is possible HD. Spermatogenesis
can contribute to increase in CAG which is passed to children. As CAG repeats increases, the age of onset lowers.
Diagnosis and symptoms
Genetic diagnosis is the presence of CAG repeats.
Clinical diagnosis is done using the UHDRS (Unified HD ranking scale):
- Motor symptoms: Chorea, Akinesia (problems initiating movement), Bradykinesia (slowness), Altered
gait, Subtle motor abnormalities.
- Cognitive symptoms: Cognitive decline. Perseverance. Reversal learning problems. Memory. Difficulties
calculating risk – can lead to gambling and addiction problems. Facial recognition. Emotional recognition
- Psychiatric symptoms: Depression. Mania. Apathy (not caring). Aggression. Suicidal thoughts. OCD.
Irritability
Juvenile HD: Happens at 20 years of age. 5-10% of cases of HD. Different clinical symptoms. Larger numbers
of CAG repeats.
Managing symptoms: Anti-chorea drugs. Anti-psychotics. Anti-depressants. Sleeping tablets. Anti-
spasticity.
Modelling HD
Models
Cellular models: Synthetically long CAG alleles – derived from patient fibroblasts. Human telomerase reverse
transcriptase used to immortalize the cells. Handy for initial drug screens but not representative of whole organisms.
Non-vertebrate models: Drosphila melanogaster - 60% genetic similarity to humans. Similar brain structure. Life span
of 50 days.
Vertebrate models: Mouse - 97.5% similar. Similar brain structure but no internal capsule. Life span of 2-3 years.
- Transgenic mouse is when the gene of interest is randomly integrated into the cell. The method is
quicker and has a higher throughput.
- Knock-in mouse is a specific integration that expands the CAG repeat. More representative of the
human model. Chimeric IT15 model contains human genes knocked into mouse gene. Insertion of CAG
contain mouse genes only.
Large vertebrate: Sheep/mini pig - Genetic & neuroanatomical similarities. Long life span of 10-20 years. Require
housing.
Primate – most similar to human brain but not usually used due to ethics. Only ever very small studies.
Behavioural tests
Motor tests: Rotor-rod and balance beam shows dexterity and gate. Grip strength. Gait analysis - look at footprints
Cognitive tests:
- Light test - mice put their nose in a hole when it lights up. Can test attention and reaction time.
- Marble burying - bury the marbles = more anxious
- Open and enclosed space – more time spent in enclosed area = more anxious
mHtt cleavage - if a long Huntington gene causes the disease, why not chop it down?
The N-terminal of normal Htt gene is very important in cellular processes. The protein that the Htt gene produces is
cleaved (split) and if it goes wrong it can cause disease. Cleavage of the Htt protein has to happen to maintain health
, Effects of mHtt: Alters endocytic and secretory pathways. Proteasomal function. Calcium handling and
mitochondrial function. Reduced transport of growth factors. Triggers apoptotic cascades, free radical production
and glutamate toxicity.
Can also lead to huntingtin inclusion formation where proteins clump in the cell and cause it die. Is this a bad thing?
Inclusions reduce the level of mutant hungtingtin
The cleaved N-terminal fragment may be more pathogenic than the full-length protein.
Inclusion physically blocks cellular machinery.
Inclusion may be formed from insufficient protein degradation.
The formation of inclusions may promote the degradation of toxic aggregates.
Overall, protects to some extent but then there comes a point where it becomes pathogenic.
R6/2 mouse models support the theory that it is the N-terminal fragment of the gene which is implicated specifically
in HD - these models have the truncated N-terminal form of the gene in their genome.
Exception: really long CAG repeats, above 335 = transgene protein that is too large for passive entry into the
nucleus via the nuclear pore.
Inclusions exist just in the cell, not in the nucleus, which results in a less severe phenotype.
Somatic expansion: When DNA repair goes wrong and repeating sections of DNA become unstable.
In regard to HD this means over your lifetime you can gain more CAG repeats - particularly high levels in the striatum
and cortex of brain. Somatic expansion usually associated with an earlier age of disease onset.
Potential therapies
Example treatments:
Pharmacological: Tetrabenazine.
Reduce hyperkinetic movement.
Promotes depletion of monoamine neurotransmitters (serotonin, norepinephrine, dopamine).
Weak binding affinity to D2 receptors
Side effects = increased risk of depression and suicidal thoughts - not good, HD already increases this risk
Non-pharmacological: exercise
Better fitness
Lower UHDRS (Unified Huntington's Disease Rating Scale) motor score
Lower weight – not good, weight loss is already a problem in HD
Potential treatments
1. Cell transplantation: replacing cells that are lost in HD, with WGEs from terminated foetuses or stem cells.
Only used in advanced cases of HD when there is no other options.
Moral and logistical issues, immunosuppression required, very invasive procedure (striatum).
Animal models create debate whether to use tissue pieces or cell suspension.
Variation in surgical technique in different parts of the world.
Results: small improvements in motor function and cognition – not enough studies
Positive case study: a decade after transplantation, the transplanted grafts were identified. It
showed that the HD cells had not overgrown/“infected” the graft cells.
Negative case study: Patient received 10 transplants - developed worsening asymmetric upper
motor neuron symptoms + progression of Huntington’s disease. He died 10 years after
transplantation and his brain showed huge overgrowth and cysts without evidence to suggest graft
rejection or HD pathology.
2. Pridopidine: Study done that suggested this drug demonstrated slowing of progression of Huntington
disease in HD patients, as measured by Total functional capacity.
Unusually high placebo effect.
Ultimately, study was dismissed due to not enough appropriate evidence.
