Huntington's Disease Flashcards
1
Q
Who discovered Huntingtons disease?
‘chorea’
A
Recognised as an inherited disorder in 1872 when a 22-year-old American doctor, George Huntington, wrote a paper called: On Chorea.
2
Q
give three basic principles of huntingtons inheritance
A
- Everyone with the mutated gene will get HD - it is autosomal dominant
- Probability of each offspring inheriting the affected gene is 50% - it is inherited
- Inheritance is independent of gender.
3
Q
what is huntingtons disease?
A
A neurodegenerative disease, caused by the aggregation of the huntingtin (HTT) protein in the human brain nerve cells. It is inherited from a persons parent in an autosomal dominant pattern
4
Q
what does chorea mean in latin and greek?
A
‘dances’
involuntary/ uncontrollable movements/ mulscle jerks and twitches
5
Q
there has been an _ in prevalence of huntingtons over the past two decades
A
increase
5
Q
there has been an _ in prevalence of huntingtons over the past two decades
A
increase
6
Q
what regions of the world have the highest prevalence of HD
A
America, Australia & most European & Western countries:
(10.6-13.7:100,000)
7
Q
what regions of the world have the lowest prevalence of HD?
A
Asia & Africa (0.5:100,000 in Japan & China)
8
Q
where is the huntingtin gene located
A
on chromosome 4
9
Q
everyone has the HTT gene, but only those that ________________ will develop HD and pass it on to their children
A
10
Q
when was the HTT gene identified?
A
1983
11
Q
when did a predictive test for the faulty HTT gene become available?
A
1993
12
Q
what does CAG code for?
A
Glutamine
13
Q
how many CAG repeats are in a normal HTT gene?
A
10-35
13
Q
how many CAG repeats are in a normal HTT gene?
A
10-35
14
Q
how many CAG repeats are in a faulty HTT gene that causes HD?
A
36 or more
15
Q
the length of the tail comes down to what?
A
how many copies of the CAG repeats there are
16
Q
why can a higher number of CAG repeats potentially lead to huntington develoment in future generations
A
CAG repeats are prone to errors at DNA replication, so number of repeats likely increases over generation/time due to replication in the germinal line
having an increased number of repeats increasese chance of a mutation occurring in them
17
Q
why can a child inherit more repeats than their parent had?
A
CAG repeats are prone to induce errors at DNA replication, so number of repeats likely increases over generations/time due to replication of the germinal line
18
Q
an elevated number of repeats affects what two aspects of the disease profile
A
more repeats = earlier onset and higher severity
19
Q
when does HD have 100% penetrance?
A
If individuals have more than 40 repeats
20
Q
when do symptoms of HD start?
A
Symptoms start between the ages of 30-50 years (40+ CAG), although late onset (36-39 CAG) and juvenile manifestation (60+ CAG) also occur.
21
Q
there is a strong inverse relationship between the age of onset and …
A
the number of CAG repeats
22
Q
how long is the prognosis from the onset of symptoms?
(usually)
A
15-20 years
23
what are the two levels of CAG repeats in unaffected individals?
Normal: 26 or less, no disease
Intermediate: 27-35, do not develop symptoms but their children are at a risk for developing huntingtons
## Footnote
there are case reports of those in the intermediate range developing mild symptoms of HD
24
what are the levels of CAG repeats in affected individuals?
reduced penetrance: 36-39, may or may not develop symptoms at any age or may develop symtoms in old age
full penetrance: 40 or more, have disease
25
what are the three stages of disease progression in HD?
Presymptomatic
Prodromal - some symptoms manifested, may or may nnot be picked up by a clinician
Manifest - motor and cognitive impairment increase as well as chorea
26
what are the two phases of huntingtons disease?
Two phases,
Early: subtle psychomotor dysfunction - signal and connectivity affected (neuronal dysfunction)
Late: manifest progressive disease as neurons begin to die, motor impairment, chorea, and decrease in functional status
27
symptomatic changes in HD affect what three main areas
1. Movement: Involuntary & Voluntary
2. Behaviour: Changes in behaviour and personality
3. Cognitive: Difficulties with planning and thinking
## Footnote
* The movement disorder is usually the most obvious first symptom.
* The behavioural disorder is usually the one that gives patients & carers the most concern.
* The cognitive disorder is usually the symptom people find affects them most in daily life.
28
why can symptoms be present a long time before diagnosis of HD?
Professionals and families can mistake HD for a different illness such as PD (parkinsons) or AD (alzheimers)
29
what are the different presentations of 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.
30
what are the different presentations of 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.
31
what are the different presentations of 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.
32
what are the major reasons of mortality in those with HD
injuries
heart disease
suicide
respiratory/ heart problems
| Respiratory/cardiac/suicide (major reasons for mortality – 3-13%).
33
what structures make up the basal ganglia?
Striatum: caudate nucleus & putamen
Globus pallidus
34
describe the series of connections that lead from the cortex to movement
activity in the cortex sends excitatory (glutamine) signals to the putamen, the putamen sends inhibitory (GABA) signals to the globus pallidus, leading to decreased inhibition and therefore excitation of the thalamus. The thalamus is primarily excitatory so it activates the motor cortex which then triggers control activation of muscle/movement.
35
the interconnected areas in volving the basal gnaglia are involved in what functions
movement, learning, thinking, planning, motivation & emotion
35
the interconnected areas in volving the basal gnaglia are involved in what functions
movement, learning, thinking, planning, motivation & emotion
36
what happens when there is degeneration of the putamen?
The area that is mostly damaged in HD is the basal ganglia – when we have degeneration of the putamen then this inhibitory activity that was activated by the cortex is going to be less inhibitory so inhibition of the globus pallidus is reduced (as globus pallidus is an inhibitory structure, inhibiting it less means more inhibition by the structure to the areas it innervates) SO the globus pallidus sends more inhibitory signals to the thalamus which means less activation of the motor cortex and less activation of the muscles and movement
Degeneration of the central hub of integration of motor activity will lead to an increase inhibition of the output that controls motor activation
## Footnote
basically less inhibition of motor movements
37
Describe the direct pathway of the basal ganglia
When the cortex send excitatory signals (glutamate) to the putamen, the putamen releases more inhibitory signals to the globus pallidus (the globus pallidus is also an inhibitory area, so inhibiting the inhibition will) lead to decrease inhibition and therefor excitation of the area that is innervates, the thalamus. The thalamus is primarily excitatory so it activates the motor cortex which then triggers control activation of muscle/movement.
## Footnote
The motor cortices send activating signals to the direct pathway through the basal ganglia, which stops inhibitory outflow from parts of the globus pallidus internus and the substantia nigra pars reticulata. The net effect is to allow the activation of the ventrolateral nucleus of the thalamus which, in turn, sends activating signals to the motor cortices. These events amplify motor cortical activity that will eventually drive muscle contractions.
38
Describe the indirect pathway of the basal ganglia
39
Describe the neuropathology of Grade 0/1 HD
GRADE 0/1: Indistinguishable from normal brains after gross examination. Selective neuronal loss in the caudate and putamen of the striatum upon histological examination.
40
describe the neuropathology of Grade 2 HD
GRADE 2: Enlargement of the lateral ventricle. Loss of cortico-striatal projection neurons. Sever gross striatal atrophy.
41
Describe the neuropathology of Grade 3/4 HD
Grade 3/4: Severe HD cases with atrophy of the striatum and wide cell loss in other cortical, cerebellum, hippocampal and hypothalamic regions.
42
what normally happens to the full length huntintin gene
it makes a normal stable protein that undergoes physiological proteostasis
43
what happens when the huntingtin has a longer poly Q tail?
An unstable/ misfolded protein is made - this leads to abnormal conformations, intracellular aggregates, betasheet structures and inclusion bodies - making the protein unable to maintain normal proteosis
44
why is there different potential situations when you inherit the faulty huntintins gene
we only have 50% normal function of huntintins
45
describe loss of function (LOF)
mutant protein no longer able to perform normal functions. This occurs in the context of a mix of normal and mutant protein
e.g. sequestering protein/s into aggregates away from where it acts; modifying protein interaction making them weaker so binding is lost
46
Describe gain of function (GOF)
extra activity imparted by the mutant protein
e.g. expanded polyQ creates protein conformers which are toxic and create new activity/interactions (albeit dysfunctional)
47
breifly describe
47
breifly describe the pathological roles of mtHTT protein
48
how can mtHTT effect the transcriptional machinery?
* - inhibition of transcription (75%)
* - inhibits histone modification, reducing transcription of genes (acetylation of genes)
eg inhibition of CREB dependent transcription (CBP)
49
describe a gain of function interaction of mtHTT
translocation of mtHTT into the nucleus where it binds to transcrition co activator CBP stopping the transcription of CRE
50
what are the pathological mechanisms in the cytoplasm when mtHTT is transcribed?
it misfolds causing aggregation into inclusion bodies - this impairs the proteostasis netwok consequently causing synaptic dysregulation, mitochondrila toxicity and axonal transport impairment
51
what happens when mtHTT or fragments of it translocate into the nucleus?
it leads to dysregulated transcription and impacts the homeostasis of the nucleus?
51
what happens when mtHTT or fragments of it translocate into the nucleus?
it leads to dysregulated transcription and impacts the homeostasis of the nucleus?
* Inhibition of transcription (75%).
* Inhibits histone modifications, reducing transcription of genes (acetylation enzymes).
* Examples include inhibition of CREB dependent transcription (CBP).
## Footnote
by control of genes that were not controlled by wild type huntingtin protein
52
mitochondria from HD patients and models of HD show what four features/differences
* Enhanced sensitivity of mPTP to Ca2+- inducing pore opening and release of CytC.
* Reduced membrane potential (ΔΨ).
* Decreased Ca2+ buffering capacity.
* Increase in ROS production (oxidative stress and degeneration of the neuron)
53
how is normal HTT anti-apoptotic?
| how does this change when there is mtHTT present?
HTT blocks procaspase 9 by direct binding
mtHTT has reduced procaspase-9 binding (LOF)
## Footnote
Mutated HTT does not perform this function leading to increase cell death
Anti-apoptotic (IAP) activity lost (LOF)
54
give five huntingtin mediated dysfunctions
- Transport deficits
- Transmitter release deficits
- Ca2+ homeostasis
- Proteasomal dysfunction signalling dysfunction
- Autophagy (protein and membrane clearance)
55
give 8 particular peculiars of medium spiny neurons
| that make them suseptible to huntingtins
- High level of glutamate cellular depolarisation.
- NMDA mediated Ca2+ influx.
- Dopamine receptors (D1 and D2)
- Selective expression of neuropeptides
- Selective expression of Ca2+ binding proteins (eg parvalbumin)
- High firing rate
- High metabolic demands
- Long projections axon (very dependent on efficient transport)
56
what explanation is there for huntingtons disease affecting some neuronal populations more than others?
The toxic effects of mtHTT do not appear to selectively affect specific neuronal populations.
Instead, cell type-specific features may differentially affect vulnerability of specific neuronal populations to mtHTT-induced toxicity.
## Footnote
cell type specific features such as afferents, targets, and biochemical content could modulate mtHTT toxicity
57
what main factor increases the vulnerability of neurons to mtHTT
neurons bearing longer and more prominent axons.
58
when was the phase1/2 trial for the gene silencing htt drug and what happened
2017, Phase1/2: In an announcement likely to stand as one of the biggest breakthroughs in Huntington’s disease since the discovery of the HD gene in 1993, Ionis and Roche announced that the first human trial of a huntingtin-lowering drug, IONIS-HTTRx, demonstrates that it reduces mutant huntingtin in the nervous system, and is safe and well-tolerated.
Jan 2019: first patients recruited onto Phase 3 trial (halted in 2021 because of safety concerns)
59
how can ASOs be used to treat a genetic disorder such as huntingtons?
antisense oligonucleotides (ASO) are allele selective drugs that bind and target mRNA for degredation
they can bind mutant HTT mRNA via single nucleotide polymorphisms and degrade it so that the damaged proteins are no longer made and inclusion bodies never form
60
what two drugs have been approved by the FDA for HD
how do they help?
Tetrabenazine (2008)
Deutetrabenazine (2017)
## Footnote
These are reversible inhibitor of the vesicle monoamine transporter type 2 (VMAT-2), inhibiting primarily dopamine and to a lesser degree serotonin and norepinephrine to treat the chorea, a primary symptom of HD.
61
what is degeneration by dying back?
neuron degenerates starting from the axon/ distal
62
what symptoms of HD can be treated with drugs?
Chorea
Behavioural disturbances: depression, anxiety, muscle tremore/seizures
Cognitive dysfunction
63
what structure is mostly degenerated in HD
basal ganglia
64
what does the direct pathway control?
filters cortical information to regulate movement /
facilitates the initiation and execution of voluntary movement.
65
what does the indirect pathway control?
it helps to prevent unwanted muscle contraction from competing with voluntary movement
66
the indirect and direct pathways are part of what neural loop
they work inconjuction with each other as part of the cortico-basal ganglia-thalamo-cortical loop.
67
describe the connectivity in the indirect pathway
68
describe the connectivity in the indirect pathway
In the indirect pathway, the motor cortices send activating signals to the caudate and putamen. The cells of the indirect pathway in the caudate and putamen that receive these signals are inhibitory and, once activated, they send inhibitory signals to the globus pallidus externus, reducing the activity in that nucleus.
The globus pallidus externus normally sends inhibitory signals to the subthalamic nucleus.
On activation of the indirect pathway, these inhibitory signals are reduced, which allows more activation of the subthalamic nucleus.
Subthalamic nucleus cells can then send more activating signals to some parts of the globus pallidus internus and substantia nigra pars reticulata. Thus, parts of these two nuclei are driven to send more inhibitory signals to the ventrolateral nucleus of the thalamus, which prevents the development of significant activity in the motor cerebral cortices.
This behavior prevents the activation of motor cortical areas that would compete with the voluntary movement
69
how do the projections from medium spiny neurons serve to release the upper motor neurons from tonic inhibition?
The projections from the medium spiny neurons of the caudate and putamen to the internal segment of the globus pallidus and substantia nigra pars reticulata are part of a “direct pathway”
The Globus pallidus acts to tonically inhibit the ventral lateral nucleus and ventral anterior nucleus of the thalamus. As these two nuclei are needed for movement planning, this inhibition restricts movement initiation and prevents unwanted movements. Striatal medium spinay neurons release GABA to the globus pallidus therefor decreasing the inhibitory singal sent to the thalamus to allow excitaory signals to be sent via upper motor neurons to initate movement
70
breifly what is the indirect pathway?
The indirect pathway passes through the caudate, putamen, and globus pallidus, which are parts of the basal ganglia. It traverses the subthalamic nucleus, a part of the diencephalon, and enters the substantia nigra, a part of the midbrain. – it helps to prevent unwanted muscle contraction from competing with voluntary movement. It operates in conjunction with the direct pathway
71
breifly what is the direct pathway?
The direct pathway, sometimes known as the direct pathway of movement, is a neural pathway within the central nervous system (CNS) through the basal ganglia which facilitates the initiation and execution of voluntary movement. It works in conjunction with the indirect pathway
72
does huntingtons affect the direct or indirect pathway
Huntington's disease results from the selective loss of striatal neurons in the indirect pathway Thus, the balance between the direct and indirect pathways becomes tipped in favor of the direct pathway
73
what are the main and earliest striatal cell type effected in HD?
Medium Spiny Neurons
74
what are the vulnerable vs spared neurons in the striatum?
| HD
the vulnerable neurons are medium spiny neurons
the spared neurons are the Aspiny neurons (they are not affected by huntingtons disease)
75
are medium spiny neurons inhibitory or excitatory?
| what neurotransmitter do they release?
they are GABAnergic neurons - inhibitory
76
broadly, what are the loss of function impacts of mtHTT
The mtHTT will be transcribed and will misfold, oligomerise and aggregate into inclusion bodies, impairing the proteostasis network, and consequently cause synaptic dysfunction, mitochondrial toxicity or axonal transport impairment
These large inclusion bodies affect all of the functions that the neuron needs to function normally.
77
broadly what are the gain of function impacts of mtHTT?
Sometimes mtHTT or fragments of it can translocate into the nucleus and control transcription of genes that were not controlled by normal HTT protein.
Leading to dysregulated transcription and impacting the homeostasis of the nucleus
There are several routes for mutated huntingtin to impact basic function: inhibtion of transcription (75%), inhibition of histone modification and reducing transcription of genes (acetylation enzymes)
78
give three examples of gain of functions of mtHTT in the nucleus
mutated HTT can translocate into the nucleus
can inhibit CREB dependent transcription (CBP) by binding to transcription factors resulting in inhibition of gene transcription
mtHTT can bind to SP! (a transcription factor) so that it can no longer regulate the transcription of the gene - inhibtiion gene transcription
mtHTT can affect epigenetic change by binding and inhibiting histone deacetylases (resulting in abberant activation of genes (becuase acetylation marks arent removed when required))
79
givean example of a loss of function mtHTT in the nucleus that affects the survival of neurons
wild type HTT usually binds the inhibitory element REST to allow transcription of the BDNF gene - a critical gene for neuron survival
mutant HTT cannot bind to REST therefore resulting in loss of function because REST binds and prevents transcription of BDNF
80
what is BDNF?
Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory
81
what is the relationship between BDNF and huntingtons?
Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration.
mtHTT also has loss of function impacts on its transcription in the nucleus
82
why could huntingtin be considered an antiapoptotic gene?
because wtHTT blocks procaspase 9 by direct binding
83
describe a mtHTT loss of function that increases suseptibility to cell death
Normal HTT under normal conditions blocks procaspase 9 by direct binding
Mutated HTT does not perform this function meaning procaspase 9 is not inhibited leading to increased susceptibility to apoptosis
