L8- Neurodegenerative Disease, HD Flashcards
HD:
- (1) general cause
- (2) and (3) changes are most evident
- (4) is the typical disease progression
1- degeneration of Striatum (caudate, putamen)
2- involuntary jerky movements
3- cognitive changes (ranges from forgetfulness to dementia)
4- death after around 15yrs
describe the genetic changes seen in HD
Huntington Gene for huntingtin protein:
- CAG trinucleotide repeats – codes for glutamine: normal is 11-34 repeats
- chr.4
- autosomal dominant w/ high penetrance
- Anticipation is major: greater the number of repeats => earlier onset and more severe Sxs
HD involves a (gain/loss) of function mutation that will interfere with (2) activity. As a result, the mutated huntingtin protein will under (3) progression. (3) will effect (4) functions in the neurons of the striatum.
1- gain of function –> expanded polyglutamine tract in huntingtin
2- nucleic acid or protein regulation
3- ubiquitination –> ineffective proteolysis –> aggregation of small/large intranuclear fragments
4- disrupt protein degradation pathway and mitochondrial function + sequester TFs + other effects
describe gross appearance of HD
- atrophy of Striatum: always Caudate, sometimes Putamen
- lesser atrophy in Globus Pallidus and cerebral cortex (frontal lobe)
- dilated lateral (1st/2nd) and 3rd ventricles
describe the microscopic features of HD
- severe loss of neurons in Striatum w/ gliosis
- intranuclear inclusion bodies in remaining neurons (ubiquinated huntingtin protein)
clinical features of HD depends on (1) and (2)
1- motor sx severity: degree of degeneration in striatum
2- dementia severity: degree of cortical neuron loss
list the motor Sxs of HD
- Chorea: involuntary jerky movements
- impaired gait, posture, balance
- difficulty in speech, eye movements
- Dystonia: muscle rigidity or contracture
list the cognitive Sxs of HD
- Early cognitive: forgetfulness
- difficulty organizing tasks, lack of impulse control
- dementia
- Early behavioral: inc risk of suicide
