Huntington's Disease - Mechanisms Flashcards
In which year was the first animal model of HD created?
1976
When was the HD gene identified?
1983
Where is the mutation in Huntingtons?
Chromosome 4
What is the penetrance of the Huntingtons mutation?
100%
CAG repeats can creep closer to the HD threshold in which sex?
Females
What does the mutation in HD code for?
Glutamine Q
What is the abnormally long CAG repeat region translated to?
Abnormally long polyglutamine tracts in the Htt protein
What is the relationship between number of repeats and age of onset?
More repeat, earlier age of onset
Which areas are most susceptible to neuronal cell death in HD?
Basal ganglia and cortex
What effect does the mutation have on Htt?
Makes it more likely/easier to aggregate
What is the main function of Htt?
Unknown
What happens in Htt KO mice?
Die
(But if switch off later in life, survives)
Where is the highest expression of Htt?
Brain and testes
Give examples of motor symptoms
Chorea Dystonia Motor impersistence Impaired gait/balace Delayed initiation of voluntary saccades
Give examples of cognitive symptoms
Loss of executive function Difficulty multitasking Rigid/inflexible thoughts Impaired spatial perception and impulsive control Deprecation of vocabulary Short term memory loss
Give examples of psychiatric symptoms
Depression
Hallucinations
Paranoia
Irritability
Outline the indirect pathways.
Motor cortex excites striatum
Striatum inhibits EGP
EGP then exhibits less inhibition on the STN
This lifts inhibition of the IGP
IGP then free to act and inhibit the thalamus to stop movement
Which part of the indirect pathway is damaged in HD?
Betw the striatum and the EGP
Outline the abnormal indirect pathway functioning in HD
Striatum cant inhibit the EGP.
More EGP activity so even inhibition of the STN
This means less activation
Outline the direct pathway
Cerebral cortec excites the striatum
The striatum sends inhibitory projection to the IGP
The IGP then cant send inhibitory signal to the thalamus
The thalamus is free to excite the motor cortex
Which pathways degenerates first?
Indirect (because d2 neurons degenerate before d1)
Where is the damage in the direct pathway?
Between the striatum and the IGP
Outline the abnormal functioning of the direct pathway in HD
Striatum unable to inhibit IGP
IGP is disinhibited and therefore increased inhibition of the thalamus
Less movement
Who originally put forward the idea that many disorders may be caused by the general concept of abnormal folding and unfolding of proteins?
Carrell and Lomas
How may proteotoxicity be suppressed in misfolding?
Suppressing the initial oligomerisation of the disease proteins and promoting their degradation
Ubiquitin degradation
Mayo et al 2015
How may mutant Htt induce cytotoxic cell death?
Induces oxidative and metabolic stress in by affecting mitochondrial function
Increases susceptibility to membrane excitability - lead to excitotoxicity
Causes cell body inclusions but pathological role unclear
Sawa et al 2003
Decreases protein degradation in cells (potentially by increasing half life)
Increases RTP801 expression (this is proapoptotic)
Alberch et al 2015
