Huntingtons Disease Flashcards
What do many HD patients show signs of before motor symptoms?
psychiatric disorders
What are some examples of motor symptoms associated with HD?
Chorea Dystonia Poor Posture Incoordination Impaired Gait and Balance
What are the cognitive symptoms of HD?
rigid, inflexible thoughts difficulty in multitasking poor concentration poor insight STM loss
What are some of the psychiatric disorders seen in HD?
depression, social isolations, delusions, hallucinations, paranoia
What can be seen in 100% of Juvenile HD cases?
rigidity
ataxia
bradykinesia
dysarthria
What are the most common signs in adult HD?
rigidity
chorea
atazia
pyramidal signs
What causes enlargement of the ventricles in HD?
the atrophy in the basal ganglia or striatum
What effect does the striatum have on the GPe?
inhibitory
What happens to the effect on the GPe in HD?
inhibitory effect is lost -> increases inhibition to STN
What effect does the GPe normally have on the STN?
inhibitory, but small inhibitory
What happens to the effect of the GPe on the STN in HD?
disinhibition of GPe leads to increased inhibition of STN
What effect does the STN have on the GPi?
an excitatory effect - diminished in HD
What happens to the effect of STN on the GPi in HD?
reduced excitatory effect due to increased inhibition from GPe
What effect does the GPi normally have on the Thalamus?
reasonable inhibition - reduced because the excitation from STN is lost
What is the normal effect of the Thalamus on the Motor Cortex?
Thalamus inhibited so reduced excitatory input to motor cortex
What happens to the effect of the Thalamus on the motor cortex in HD?
decreased inhibition from GPi causes extra excitation
What does the indirect pathway account for in the HD?
the increased involuntary movement from the chorea
What is the normal effect of the Striatum on the GPi in the direct pathway?
normally inhibitory which inhibits the GPi
What is the effect of the Striatum on the GPi in HD?
inhibition lost so GPi can send large inhibitory input to thalamus
What influence does the GPi normally have on the thalamus in the direct pathway?
slight inhibitory effect, normally disinhibited by striatum
What effect does the GPi normally have on the thalamus in HD?
large inhibitory effect as GPi is not inhibited in thalamus
What is the net result of the direct pathway in HD?
less stimulation to motor cortex - reason it is difficult to initiate voluntary movement
What accounts for the fact that chorea appears first?
The striatal cells that project to the GPe die before the ones that project to the GPi
When do neurons start to struggle in HD?
in the prodromal phase - symptoms are not totally noticeable
How is HD diagnosed?
neurological exam, family history and genetic testing
Why will patients younger than 18 not be tested?
there is no treatment for either the prodromal or the symptomatic phase
Why is indirect genetic testing of the fetus possible?
for parents who may have HD but wish to be undiagnosed
What can early motor symptoms such as chorea be treated with?
tetrabenazine -> reduces DA release
What sorts of therapies are in the pipeline for HD?
gene silencing, PDE inhibitors, Stem cells research
Where is the substantia nigra in comparison to the striatum?
upstream
What effect does the SN have on the striatum?
it inhibits it by releasing dopamine via D1 and D2 receptors
Which DA receptors are on the GPe?
D2
Which DA receptors are on the GPi?
D1
What is the effect of tetrabenazine?
inhibits the SN by reducing DA production and inhibiting receptors so that the striatum is disinhibited and restores normal function for a while
How is HD inherited?
autosomal dominant mutation on chromosome 4
What is the penetrance of the HD gene?
100%
What is the mutation in HD?
CAG repeats > 36 (>40 for testing)
Which part of the gene is the mutation in (HD)?
exon 1 of the htt gene
What does the length of the CAG repeat do?
determines severity and age of onset
Why is Htt vital?
KO is embryonic lethal
Where is the highest expression of Htt?
brain and testes
What is the issue with targeting mutant Htt?
the difference between it and WT is the number of CAG repeats - how do you get something to target that
What happens to mutant Htt?
very long protein so can be misfolded and start to aggregate
Where within the neurons does Htt accumulate?
in the nuclei of neurons
What does Htt aggregation lead to?
neuronal death
What is involved with gene silencing?
using anti-sense oligonucleotides (similar to ALS)
How do anti-sense oligonucleotides work in HD?
reduce the overall amount of Htt by blocking mRNA from producing the protein
What was found in Animal studies of ASO in Htt?
Silencing of Htt lasted 4 months
Who did the animal studies in Htt ASO?
Kordasiewicz et al 2012, Neuron
What was found in the YAC128 HD mouse with ASO?
improvement of the motor phenotype correlated with reduction in mHtt levels
Who conducted the YAC128 mouse study with ASO?
Stanek et al. 2013, J of HD
How might patients be given ASO in future?
epidural injection of ASO tagged with a protein that can cross the BBB - ie brain shuttle
What needs to be considered in terms of ASO distribution?
whether it reaches the striatum (rats and mice suggest it does not) - if it doesn’t will it make any difference
What needs to be considered in terms of ASO and how it attacks the protein?
What is going on with WT?
are both turned off?
is WT Htt reduced anyway?
are there side-effects to switching off WT Htt?
What considerations need to be taken into account when choosing the target of ASO?
where should the ASO target? SNPs or the CAG repeat?
What are the considerations in terms of ASO and side-effects?
does it have off-target effects and other mRNA
what about immune responses?
What are the potential models for studying HD?
cell lines
invertebrates
stem cell
What are the advantages of using cell lines?
- immortalised cells which can be human or non-human
- easy to manipulate
- used to dissect the molecular machinery involved
What are the advantages of using invertebrates?
- whole organism with quick reproduction
- simpler genetic manipulation
- quick to understand the pathways in the whole animal
What are the advantages of using Stem cells?
- can be derived from patient fibroblasts
- induced pluripotency to generate neurons
- directly test drug effects
What are the options of mouse model in HD?
N-terminal transgenics
Full length transgenics
Knock Ins
What are the limitations of mouse models of HD?
- mice do not respond to HD the same way as humans - neuronal death occurs at end stages
What is the advantages of using an N-terminal transgenic?
more severe symptoms more quickly so quicker research
What is the advantage of using full length transgenics?
closer to human disease but milder symptoms that develop laters
What is the YAC128 mouse?
full length transgenic that expresses full length human HTT with 100 and 126 CAG repeats but also has 9 interspersed CAA
expresses transgene at roughly same level as endogenous mouse Htt (75%)
What needs to be considered in the YAC128 mouse?
whether the CAG-CAA combination alters the mRNA toxicity in HD
What phenotypes can be seen in YAC128?
motor impairement procedural learning deficit Impaired strategy shifting depression like behaviour anxiety like behaviour increased body weight - Pouladi et al. 2013 Nat Rev Neurosci
Review for all the YAC128 behaviour phenotypes?
Pouladi et al. 2013 Nat Rev Neursci
What is the feature of the N-terminal transgenic?
carries small portion of 5’ end of human Htt gene - exon 1 the CAG repeat
What is the phenotype of the N-terminal transgenic?
loss of coordination, tremors, hypokinesis, abnormal gait, neuropathology and premature death
What are the potential models of N-terminal transgenics?
R6/2, R6/1
What is the issue with CAG instability in the R6/2 transgenic?
CAG repeat length can vary from 40-600 although more stable if bred through female line
What are the features of the Knock In?
can be heterozygous for Htt and WT - important as this is common in humans - can explore WT Htt contribution to HD
What is the control for studies with Knock ins?
HdhQ82 - basically fine - no HD
What is the issue with Knock INs?
need so many repeats - at least 100 to show signs of disease at old age
What did studies show with Q111 locus?
in the striatum, pyramidal tracts of the CA1 neurons
Where do Q111 phenotypes not have issues in cognition
novel object recognition is fine in homo, het at 2/13 months
What issues does the Q111 phenotype have in cognition?
- object place recognition in homo and het at 13 months not 2 months
- object context recognition at 13 months in homo and het
- object place context in homo and het at 2 and 13 months
What was shown to happen to hippocampal LTP in Q111?
homo and hets only showed a small % increase of fEPSP
What happens to Q111 mouse when a5IA applied?
improves fEPSP in homo and a little in het
translates into an improvement in episodic memory at 2months
