Diego - Huntingtons & Amyloid Beta Flashcards
(28 cards)
What is huntingtons disease?
It is a autosomal dominant, hereditary, neurodegenartive disease
- Everyone with the mutated huntingtons gene will get huntingtons
- Probability of each offspring inheriting the affected gene is 50%
- Inheritence is independant of gender
- Characterised by cognitive, behavioural and motor dysfunction
What is the prevelance of HD?
Increase in prevelance of HD over the past two decades
Family history normally - likely excluded sporadic or de novo cases (5-8%)
Prevelance studies show:
- Higher prevelance in America, Australia & most of European & Western countries (10.6-13.7 per 100,000)
Lower prevelance in Asia & Africa (0.5 per 100,000 in Japan and China)
Where is the huntingtons disease located?
The huntingtons disease gene is located on chromosome 4
Everyone has the HTT gene, but only those that inherit the expansion of the gene will develop HD and perhaps pass it on to each of their children
The gene was identified in 1983 and a predictive genetic test became available in 1993
What is meant by ‘expansion and anticipation’ in Huntington’s disease?
Refers to the worsening and earlier onset of symptoms in each new generation
Huntington’s is linked to CAG repeat expansion in a gene
27–35 repeats:
- Considered a “grey zone”
- Individuals usually don’t show symptoms
- But future generations are at risk due to further repeat expansion
36-39 repeats:
- Typically results in symptomatic Huntington’s disease
- Higher repeat numbers correlate with earlier and more severe disease onset
- May or may not develop symptoms at any age
40+ repeats:
- Individuals will have the disease (100% penetrance)
What is the age of onset and prognosis of huntingtons disease?
Symptoms start between the ages of 30-50 years (40+ CAG), although late onset (36-39 CAG) and juvenile manifestations (60+ CAG) do occur
Prognosis is usually between 15-20 years from symptom onset
What is the clinical progression of huntingtons disease?
Presymptomatic stage:
- Individual carries the mutation but shows no symptoms
Prodromal stage:
- Early pathological changes begin
- Symptoms may be subtle or undetectable
- Disease is not yet diagnosable, but changes are occurring
Manifest stage:
- Clear clinical symptoms emerge
- Disease is detectable and progressively worsens over time
Progression:
- Pathology begins in the prodromal stage, below detection threshold
- Becomes clinically apparent during the manifest stage
What is the neurobiological progression of huntingtons disease?
Neuronal dysfunction precedes neurodegeneration
- Neurons begin to function abnormally before they die
This early dysfunction leads to psychomotor symptoms
- Occurs before the onset of overt motor symptoms like chorea
As the disease progresses, neurodegeneration worsens, leading to more pronounced motor and cognitive impairments
What are the symptoms of huntingtons disease?
The symptoms of HD vary widely between people, even within families
Changes usually affect three main areas:
- Movement (Involuntary & Voluntary)
- Behaviour (Changes in behaviour and personality)
- Cognitive (Difficulties with planning and thinking)
Symptoms may be present for a long time before a diagnosis of HD
Professionals and families may mistake HD for a different illness such as parkinsons disease or alzheimers disease
- The movement disorder is usually most obvious first symptom
- The behavioural disorder is usualy the symptom that causes most worry amongst patients and carers
What are the physical symptoms of HD?
The symptoms of HD are like having ALS, PD & AD simultaneously.
- Motor deficits (jerky/fidgety motor).
- May seem clumsy or stumble more than usual.
- Voluntary movement are affected.
- Abnormal eye movement.
- Speech becomes slurred.
- As disease progresses, swallowing problems become common.
- Weight loss (excessive movements and malnutrition through dysphagia) and central effects on appetite.
- Incontinence.
- Involuntary movements cannot be consciously suppressed and stop only with sleep.
What are the cognitive symptoms of HD?
- Memory and concentration problems
- Hard to plan and think ahead, difficult to switch between tasks.
- Lack of motivation - appear lazy.
- Reduced ability to read facial expression.
- Emotional changes -subtle changes to mood/behaviour.
- Aggressive, demanding, stubborn and self-centred.
- Impulsive or irrational, behaving in a disinhibited way or obsessive with things. depression, anxiety and anger.
- Relationships at high risk.
- May lead to social isolation.
- Respiratory/cardiac/suicide (major reasons for mortality - 3-13%).
How does the basal ganglia regulate movement under normal conditions?
- Key structures: Cortex → Putamen → Globus Pallidus → Thalamus → Motor Cortex
- Cortex uses glutamate (excitatory) to stimulate the putamen
- Putamen responds by releasing GABA (inhibitory) to the globus pallidus
- Globus pallidus, also inhibitory, now receives inhibition → it sends less GABA to the thalamus
- Thalamus, relieved from inhibition, activates the motor cortex → enables muscle control
- This is a finely tuned balance of excitation and inhibition that regulates smooth movement
What happens to basal ganglia circuitry in Huntington’s disease?
- Putamen neurons degenerate → reduced GABA release
- Leads to less inhibition of the globus pallidus
- Globus pallidus now becomes more active, increasing GABA sent to the thalamus
- This causes over-inhibition of the thalamus, reducing its activation of the motor cortex
- Result: Impaired motor control, contributing to motor symptoms in Huntington’s disease
- Also affects non-motor circuits projecting to cognitive areas of the cortex
Is neuronal death in the striatum during Huntington’s disease uniform across all neuron types?
No — it is selective
The striatum contains two main neuron types:
Medium spiny neurons (MSNs):
- Make up ~95% of striatal neurons
- GABAergic (inhibitory)
- Highly vulnerable to degeneration in Huntington’s disease
Aspiny neurons:
- Fewer in number
- Located in the same area, but resistant to degeneration
Both neuron types carry the same mutation, but only MSNs degenerate
Selectivity likely relates to cell-type-specific functions, connectivity, and possibly transcriptional vulnerability
How is HD neuropathology characterised?
Characterised in 1985 based off of loss of matter
GRADE 0/1:
- Indistinguishable from normal brains after gross examination.
- Selective neuronal loss in the caudate and putamen of the striatum upon histological examination.
GRADE 2:
- Enlargement of the lateral ventricle. Loss of cortico-striatal projection neurons.
- Severe gross striatal atrophy.
Grade 3/4:
- Severe HD cases with atrophy of the striatum and wide cell loss in other cortical, cerebellum, hippocampal and hypothalamic regions.
What is “polyQ” in the context of Huntington’s disease?
“PolyQ” stands for “polyglutamine”
It refers to a repeated sequence of the amino acid glutamine (Q) in a protein
Encoded by the DNA triplet CAG, which codes for glutamine
In the huntingtin (HTT) gene, a normal number of repeats is usually ≤35
In Huntington’s disease, the HTT gene has 36 or more CAG repeats → leads to polyglutamine expansion
The longer the polyQ stretch, the more unstable and misfolded the protein becomes
This misfolding leads to aggregation, cellular toxicity, and ultimately neuronal death
What are the molecular consequences of polyglutamine (polyQ) expansion in the huntingtin protein?
The mutant huntingtin protein has an expanded polyQ (CAG) repeat region
This causes the protein to become structurally unstable and misfold
Misfolded huntingtin:
- Forms intracellular aggregates called inclusion bodies
- These aggregates often contain β-sheet structures
Aggregates disrupt proteostasis (protein quality control), affecting not only huntingtin but overall cellular protein homeostasis
Loss of function:
- The normal role of huntingtin is compromised
- Protein degradation pathways are impaired
Gain of toxic function:
- Aggregates may interact abnormally with other proteins
- Lead to cellular dysfunction across multiple pathways
What are inclusion bodies in Huntington’s disease and when do they form?
- Inclusion bodies are insoluble aggregates of misfolded mutant huntingtin protein
- Found in the cytoplasm of neurons in Huntington’s disease brains
- Often marked by ubiquitin, a protein tag for degradation
- Their presence indicates proteostasis dysfunction
- Similar inclusions are seen in mouse models with engineered HTT mutations
- Commonly appear when CAG repeats exceed ~40
- Repeats in the 35–46 range may form inclusions
- However, not all individuals with repeats in this range develop symptoms during their lifetime
What are ‘loss of function’ and ‘gain of function’ in Huntington’s disease, and why are they important?
The mutant huntingtin protein doesn’t just stop working — it changes how it works
Two major consequences:
1. Loss of Function (LOF):
- The mutant protein can no longer carry out the normal roles of huntingtin
- Even though some normal protein is still present, the mutant version can:
- Sequester proteins into aggregates, removing them from where they’re needed
- Weaken normal protein interactions, causing functional loss
2. Gain of Function (GOF):
- The mutant protein acquires new, harmful functions
- Expanded polyQ region causes misfolding into toxic conformers
- These misfolded proteins form abnormal interactions or trigger cellular stress
- Result: Neurotoxicity, despite the protein still being “active”
- Together, LOF + GOF explain the selective dysfunction and cell death seen in Huntington’s disease
What cellular effects does mutant huntingtin have in medium spiny neurons?
Expanded polyQ region causes mutant huntingtin to misfold and form β-sheet structures
Leads to protein aggregation → formation of large intracellular inclusions
These inclusions:
- Overwhelm and saturate the proteostasis system
- Disrupt degradation of other essential proteins
- Cause widespread cellular dysfunction (e.g. cytoplasmic activity, mitochondrial function, axonal transport)
Mutant huntingtin can also translocate to the nucleus, where it:
- Alters transcription of genes normally regulated by wild-type huntingtin
- May gain new, harmful regulatory effects on gene expression
- Disrupts normal neuronal gene programs, affecting differentiation and survival
How does mutant huntingtin affect transcription in neurons?
~75% of transcriptional effects from mutant huntingtin are inhibitory
Interferes with multiple aspects of gene regulation:
- Inhibits transcription of many genes
- Disrupts histone modifications, affecting epigenetic memory
Specifically inhibits CREB-dependent transcription:
- Mutant huntingtin enters the nucleus
- Binds to CBP, a coactivator of phosphorylated CREB
- This prevents CREB from activating target genes
CREB is a widely used transcription factor in neurons — its inhibition affects key pathways involved in cell survival and plasticity
How does mutant huntingtin affect transcription through gain of function mechanism?
Gain of Function (GOF):
- Mutant huntingtin acquires new transcriptional roles not seen in the wild-type protein
Example:
- Binds to SP1, a transcription factor near TBP (TATA-binding protein)
- This abnormal interaction activates RNA polymerase II transcription, even though wild-type huntingtin is not normally involved
How does mutant huntingtin affect transcription through loss of function mechanism?
Loss of Function (LOF):
Wild-type huntingtin normally binds REST, a repressor of RNA polymerase II
This binding inhibits REST, allowing proper gene transcription
In mutant huntingtin, REST binding is lost → REST now binds to RE1 elements
- This inhibits transcription of REST-target genes
Mutant huntingtin also disrupts histone modification, e.g.,
- Inhibits histone deacetylases (HDACs)
- Affects epigenetic regulation and memory encoding
How does mutant huntingtin affect mitochondrial function and contribute to neuronal damage?
Mutant huntingtin aggregates in the cytoplasm can disrupt mitochondrial function
This effect is independent of proteostasis disruption
Key consequences:
- Binds to mitochondrial pores, causing abnormal opening
- Leads to release of cytochrome c, which can trigger apoptosis
- Reduces mitochondrial membrane potential
- Decreases calcium buffering capacity, making cells more vulnerable to calcium overload
- Promotes production of reactive oxygen species (ROS) → oxidative stress
This is another gain of function of mutant huntingtin
Contributes to neuronal toxicity and cell death
How does the loss of wild-type huntingtin’s anti-apoptotic function contribute to neuronal death in Huntington’s disease?
Wild-type huntingtin has a protective, anti-apoptotic role
- It binds to procaspase-9, preventing its activation into caspase-9
- This blocks the intrinsic (mitochondrial) apoptosis pathway
In mutant huntingtin, this binding is lost →
- Procaspase-9 is no longer inhibited
- Leads to activation of caspase-9 and initiation of apoptosis
This is a loss of function mechanism
Directly contributes to neuronal vulnerability and degeneration
