Neuroscience - Huntingtons Flashcards
How common is Alzheimers? What regions of the brain are most affected? What proteins are involved? What are the pathological agents?
- 0.5%
- Cortex, hippocampus, basal forebrain
- Amyloid precursor protein
- Presenilin 1 and 2
- Amyloid plaques
- Neurofibrillary tangles
How common is Parksinsons? What regions of the brain are most affected? What proteins are involved? What are the pathological agents?
- 0.2%
- Substantia nigra
- cortex
- alpha-synuclein
- parkin
- Lewy bodies
How common is Huntingtons? What regions of the brain are most affected? What proteins are involved? What are the pathological agents?
- 0.01%
- Striatum
- Other basal ganglia
- cortex
- Huntingtin - single gene
- Intranuclear inclusions
- Cytoplasmic aggregates
What are the 3 main clinical features of HD?
- Motor dysfunction
- Cognitive dysfunction
- Psychiatric problems
Give some examples of features within these main features
Motor dysfunction:
- Chorea (involuntrary movements)
- Abnormal gait
- Poor coordination
- Rigidity
- Abnormal eye movements
- slurred speech
Cognitive dysfunction:
- dementia
- depression
- mental slowing
- decline in attentive behaviour
Psychiatric problems:
- Personality change
- Mood swings
- Social withdrawal
- Suicide/self harm
What are the motor components of the basal ganglia?
1) Striatum
- caudate
- putamen
2) Pallidum
- globus pallidus
- substantia nigra pars reticulata
3) Substantia nigra pars compacta
4) Subthalamic nuclei
What neurons degenerate in HD?
The medium spiny neurons of the striatum mainly
- others do degenerate
What occurs in the brain of HD patients?
1) Medium spiny neurons degenerate
2) Reduced inhibitory output from striatum
3) Decreased inhibition of globus pallidus external segment i.e more active
4) Increased inhibition of globus pallidus internal segment
- directly through external segment
- indirectly through decreased excitatory input from subthalamic nucleus
5) Reduced inhibition of thalamus/cortex
6) Overactivity of motorneurons
How does this pathway differ in Parkinsons?
- The dopaminergic neurons of the substania nigra pars compacta degenerate
- Usually provides both excitatory and inhibitory signals to the striatum
- Reduced activation of direct pathway and increased inhibition through the indirect pathway
- Underactivity of motorneurons
What chromosome is the huntingtin gene found on?
4
What does it encode?
Huntingtin
- a cytosolic protein
- ~348kDa
- expressed in developing and adult brain
What gene mutation causes mutated huntingtin?
> 40 CAG repeats codes for protein with glutamine repeats
What determines the age of onset and severity of degeneration in huntingtons?
The length of the repeat
e.g (CAG)n
What occurs to huntingtin (HTT) do cause pathogenesis?
- Subject to proteolytic cleavage
- Full length or fragments, such as HTT exon 1, of mutant HTT form aggregates or large inclusions
- Cytoplasmic aggregates impair processes such as protein/folding/degradation, vesicular trafficking, metabolism etc
- Translocation of fragments to nucleus disrupts gene expression
How does wild type HTT upregulate Brain Derived Neurotrophic Factor (BDNF)?
- HTT forms complex with RILP
- RILP interacts with REST, preventing its nuclear translocation
- If allowed to translocate, would repress BDNF
