Exam 1: Huntington's Disease Flashcards
How is it inherited?
autosomal dominant
no effective treatment
10-13/100,000
When do symptoms show up
3rd-4th decade
Symptoms
Initial: loss of coordination, mood swings, anxiety, irritability, depression, involuntary twitching, desultory thought and short term memory loss
later: loss of concentration and memory, increased involuntary , aggression, and anti-social behavior, loss of speech and swallowing, can’t care for self
death 10-20 years: pneumonia, suicide, infection, chocking, heart failure
Where lies this genetic anomaly?
short arm chromosome 4- extended polyglutamine tract
26 repeats: normal
risky in the middle
40+ = will have HD
Issues with genetic testing
survivors guild insurance duty to warn stressful family abandonment
What is the deal the CAG repeats?
more in Caucasians
intermediate alleles at high risk for de novo passed through father from CAG repeat instability in spermatogenesis
length of CAG repeats influences ONSET
more repeats = early onset
What types of cell death are in huntington’s
1) early stage loss of medium spiny neurons (GABAergic) coexpressing enkephalins (INDIRECT PATHWAY).
2) Later stage loss of medium spiny neurons co-expressing SUBSTANCE P (DIRECT PATHWAY)
uninhibited thalamus, excited cortex
involuntary hyperkinetic movement
HTT RNA transcript gene
mRNA encodes huntington protein
mRNA encode only exon1 whEn expanded CAG repeat
Proteolytic cleavage series of products, including HTT exon1-like fragments. have EXPANDED POLYq SEGMENTS
How do these HTT proteins and exon1 fragments do crazy?
cleaved into fragments near nucleus and enter
form inclusions, causes transcriptional dysregulation by sequestering other proteins
fragments oligomerize and aggregate in cytoplasm
aggregation exacerbated through impairment of proteostasis network
Aberrant Huntington produces other global cellular impairments
Huntington’s 3 mechanisms of cell death
Polyglutamines give toxic gain of function to mutated protein through poorly understood mechanisms
1) Aggregation of glutamines sequesters other proteins needed for cell function
2) Mitochondrial impairment produced through down-regulation of electron chain enzymes (decrease ATP increase ROS)
3) Glutamate-induced excitotoxicity resulting from reduced ATP production impairs K-NaATPase, inhibiting neurons’ ability to repolarize and release voltage-dependent Mg+ (opens Ca2+, free radicals)
Treatments of Huntington’s
symptomatic and ineffective
tranquilizers, antipsychotics and antidepressants
Tetrabenazine
for hyperkinetic disorders, approved in 2008.
Depletes monoamines by blocking VMAT2
Areas of research in Huntington’s
1) Dopamine Depletion through antagonists/uptake inhibitors - side effect problem.
2) NMDA antagonists appear helpful but inconsistent
Neuroprotective therapies: Coenzyme Q10
enzyme involved in mitochondrial electron transport
Animal studies ongoing
Neuroprotective therapies: BDNF
trophic factor essential for striatal neurons
mutant Huntington’s protein disrupts BDNF transport
Animal models have given promising results, no clinical trials
