Lecture 5- Huntington's Disease

Question 1

background of HD

Answer 1

monogenic disorder, autosomal dominant, genetic stutter, 10-20yrs progression

Question 2

symptoms of HD

Answer 2

psychiatric (depression), cognitive deficits, movement disorder (chorea)

Question 3

genetics of HD

Answer 3

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

Question 4

brain regions affected

Answer 4

inner-cordate putamen (makes up striatum- part of basal ganglia)
outer- cerebral cortex

Question 5

synpatopathy

Answer 5

disorder of synapses

Question 6

circuitopathy

Answer 6

disorder of circuits

Question 7

corticostriatal loop

Answer 7

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

Question 8

pathological plasticity covers (2)

Answer 8

1- adult neurogenesis

2- synaptic plasticity

Question 9

adult neurogenesis

Answer 9

birth of new neurons in certain regions of brain

Question 10

synpatic plasticity

Answer 10

way in which neurons are wired, connections via synapses

Question 11

what can pathological plasticity cause?

Answer 11

cellular dysfunction, cognitive and psychiatric symptoms

Question 12

transgenic HD mice

Answer 12

R6/1 mice- similar brain circuits, 95% same genome, test movement/motion/cognition
express human exon 1 transgene encoding expanded polyglutamine

Question 13

genetic construct validity

Answer 13

use animal model that has human mutation

Question 14

face validity

Answer 14

show over time mice develop cognitive problems, affective signs etc just like humans

Question 15

abnormal vocalisation

Answer 15

precedes motor onset in HD mice

Question 16

touchscreen chambers

Answer 16

learn cognitive tasks and get rewarded, similar to human cognitive tasks
- translational implications to humans

Question 17

disease onset and progression in HD mice

Answer 17

affective/cognitive abnormalities–>motor deficits–>decreased cortical and striatal volume–>neuronal death–>end-stage disease

Question 18

genetic contribution to HD

Answer 18

thought to be 100% genetic, but environmental factors

Question 19

environmental contribution to HD

Answer 19

modulate age of onset of disease
positive modulators- physical activity, stimulation, caloric restriction
negative modulators- obesogenic diet, sedentary lifestyle, high stress

Question 20

why is a delay in onset good>

Answer 20

would be a ‘cure’ since you just die of old age

Question 21

standard housing vs environmental enrichment

Answer 21

standard- normal bedding etc

EE- toys, opportunity for cognitive stimulation

Question 22

EE and activity levels

Answer 22

enhances activity levels

Question 23

EE and onset in HD mice

Answer 23

delays onset- by measuring loss of motor coordination (chorea)
- through physical activity and cognitive stimulation

Question 24

EE and cerebral cortex volume in HD mice

Answer 24

salvages loss of cerebral cortex volume in HD mice

- env reduced shrinkage of CC around striatum

Question 25

EE and protein aggregation/clearance in HD mice

Answer 25

- small but significant change in size (measuring aggregates of abnormal protein)

Question 26

Wexler study evidence for environmental modifiers in HD

Answer 26

analysed venezuelan kindreds- founder effect | - remaining variance in age of onset not explained by CAG repeat length

Question 27

Trembath et al study evidence for environmental modifiers in HD

Answer 27

retrospective study of NZ and aus families | - passivity (reduced activity) risk factors, contributes to earlier age of HD onset

Question 28

EE, neurogenesis and synaptic plasticity

Answer 28

experience dependent regulation | - enhances both neurogenesis and synaptic plasticity

Question 29

brain target regions for HD gene expression

Answer 29

neocortex (frontal, parietal, occipital) hippocampus striatum

Question 30

EE and cognitive deficits

Answer 30

EE delays onset of hippocampal dependent cognitive deficits in HD mice - delayed onset of dementia in HD

Question 31

2 proteins- molecular mediators of synaptic plasticity

Answer 31

GluR1 and PSD95- important in forming memory and cognition

Question 32

GluR1

Answer 32

protein level down in hippocampus

Question 33

PSD95

Answer 33

protein level down in hippocampus | upregulated by enrichment

Question 34

DARPP-32

Answer 34

dopamine and cAMP regulated neuronal phosphoprotein - protein levels affected in anterior cortex - protein rescued by EE in striatum

Question 35

BDNF

Answer 35

brain derived neurotrophic factor - levels disrupted in non-enriched HD - rescued by EE in anterior cortex and hippocampus (model of depression and antidepressant action)

Question 36

HD and stress

Answer 36

decreased neurogenesis, depression/cognitive deficits

Question 37

SSRI

Answer 37

selective serotonin reuptake inhibitor- antidepressant | - rescues depression like behaviour in female HD mice

Question 38

EE and SSRIs

Answer 38

increased neurogenesis, cognitive effects (antidepressant)

Question 39

enhanced voluntary physical exercise

Answer 39

delays onset of short term spatial memory deficit | -reduces abnormal stress response

Question 40

sexually dimorphic HPA axis dysfunction

Answer 40

female- stress levels decrease then increase post-stress induction male- stress levels progressively decrease post-stress induction

Question 41

elevated stress hormone levels

Answer 41

accelerates cognitive decline

Question 42

EE and adrenals

Answer 42

experience dependent adrenal dysfunction; EE can directly affect adrenals via epigenetic mechanism