Lecture 5- Huntington's Disease Flashcards
background of HD
monogenic disorder, autosomal dominant, genetic stutter, 10-20yrs progression
symptoms of HD
psychiatric (depression), cognitive deficits, movement disorder (chorea)
genetics of HD
CAG/glutamine repeat in huntingtin gene
- normal 10-30 CAGs
-HD >40 repeats, encodes more glutamines
brain regions- most toxic to cerebral cortex and striatum but also outside
brain regions affected
inner-cordate putamen (makes up striatum- part of basal ganglia)
outer- cerebral cortex
synpatopathy
disorder of synapses
circuitopathy
disorder of circuits
corticostriatal loop
striatum to cortex and back around
- implicated in motor/cognitive function, movement, affective function (depression)
- dysfunction of cells and death of neuronal population (disrupt loop)–>motor and cognitive dysfunction
pathological plasticity covers (2)
1- adult neurogenesis
2- synaptic plasticity
adult neurogenesis
birth of new neurons in certain regions of brain
synpatic plasticity
way in which neurons are wired, connections via synapses
what can pathological plasticity cause?
cellular dysfunction, cognitive and psychiatric symptoms
transgenic HD mice
R6/1 mice- similar brain circuits, 95% same genome, test movement/motion/cognition
express human exon 1 transgene encoding expanded polyglutamine
genetic construct validity
use animal model that has human mutation
face validity
show over time mice develop cognitive problems, affective signs etc just like humans
abnormal vocalisation
precedes motor onset in HD mice
touchscreen chambers
learn cognitive tasks and get rewarded, similar to human cognitive tasks
- translational implications to humans
disease onset and progression in HD mice
affective/cognitive abnormalities–>motor deficits–>decreased cortical and striatal volume–>neuronal death–>end-stage disease
genetic contribution to HD
thought to be 100% genetic, but environmental factors
environmental contribution to HD
modulate age of onset of disease
positive modulators- physical activity, stimulation, caloric restriction
negative modulators- obesogenic diet, sedentary lifestyle, high stress
why is a delay in onset good>
would be a ‘cure’ since you just die of old age
standard housing vs environmental enrichment
standard- normal bedding etc
EE- toys, opportunity for cognitive stimulation
EE and activity levels
enhances activity levels
EE and onset in HD mice
delays onset- by measuring loss of motor coordination (chorea)
- through physical activity and cognitive stimulation
EE and cerebral cortex volume in HD mice
salvages loss of cerebral cortex volume in HD mice
- env reduced shrinkage of CC around striatum
EE and protein aggregation/clearance in HD mice
- small but significant change in size (measuring aggregates of abnormal protein)
Wexler study evidence for environmental modifiers in HD
analysed venezuelan kindreds- founder effect
- remaining variance in age of onset not explained by CAG repeat length
Trembath et al study evidence for environmental modifiers in HD
retrospective study of NZ and aus families
- passivity (reduced activity) risk factors, contributes to earlier age of HD onset
EE, neurogenesis and synaptic plasticity
experience dependent regulation
- enhances both neurogenesis and synaptic plasticity
brain target regions for HD gene expression
neocortex (frontal, parietal, occipital)
hippocampus
striatum
EE and cognitive deficits
EE delays onset of hippocampal dependent cognitive deficits in HD mice
- delayed onset of dementia in HD
2 proteins- molecular mediators of synaptic plasticity
GluR1 and PSD95- important in forming memory and cognition
GluR1
protein level down in hippocampus
PSD95
protein level down in hippocampus
upregulated by enrichment
DARPP-32
dopamine and cAMP regulated neuronal phosphoprotein
- protein levels affected in anterior cortex
- protein rescued by EE in striatum
BDNF
brain derived neurotrophic factor
- levels disrupted in non-enriched HD
- rescued by EE in anterior cortex and hippocampus (model of depression and antidepressant action)
HD and stress
decreased neurogenesis, depression/cognitive deficits
SSRI
selective serotonin reuptake inhibitor- antidepressant
- rescues depression like behaviour in female HD mice
EE and SSRIs
increased neurogenesis, cognitive effects (antidepressant)
enhanced voluntary physical exercise
delays onset of short term spatial memory deficit
-reduces abnormal stress response
sexually dimorphic HPA axis dysfunction
female- stress levels decrease then increase post-stress induction
male- stress levels progressively decrease post-stress induction
elevated stress hormone levels
accelerates cognitive decline
EE and adrenals
experience dependent adrenal dysfunction; EE can directly affect adrenals via epigenetic mechanism
