Lecture 4 Flashcards
Symptoms of HD
Uncontrolled movements, emotional problems, and loss of thinking ability (cognition)
Who discovered HD
George Huntington
What did George Huntington describe HD as
Hereditary form of chorea
Chorea
Dance-like movements
Huntingtons “peculurarities”
- Hereditary nature
- Tendency toward insanity and suicide
- Manifestation as a fatal disease in adult life
Origin of HD chromosome
European origin
Where is the highest prevalance of HD
Maracaibo region of Venezuela
How many cases of HD in venezuela
700 per 100,000
Mutations in __ gene cause HD
HTT
HTT provides intiructions for making a protein called
Huntingtin
Role of huntingtin
Unknown, thought to play a role in neurons in the brain
Mutation of HTT involves __ repeat
CAG trinucleotide
Normal CAG repetition
10-35 times
CAG repetition in HD
36-120 times
People with __-__ CAG repeats may not develop symptoms
36-39
People with __ or more repeats of CAG almost always develop the disorder
40
More repeats of CAG =
Earlier onset, faster progression, and more severe HD
What amino acid does CAG code for
Glutamine
Testing for amplifications in CAG
PCR and electrophoresis
__% of patients with HD have an expanded allele with 36 or more CAG repeats
99%
Type of inheritance of HD
Autosomal dominant (usually passed from one affected parent)
What happens to the size of the CAG repeat as it is passed from one generation to the next
Increases
Can you get HD if you dont have a parent with HD
Yes but it is rare
What is it called when the amount of CAG repeats increases from one generation to another
Expansion
A larger number of repeats is associated with earlier onset of signs and symptoms. This is called ___
Anticipation
What does expanision of CAG segment lead to
Production of abnormally long version of the huntingtin protein
What happens to the elongated huntingtin in the cell
Cut into smaller, toxic fragments that bind together and accumulate in neurons
Name for aggreates of huntingtin
Inclusions
Where do inclusions start accumulating
Dendrites and axons
Where do inclusions move from the dendrites and axons
To the nucleus
What happens to a neuron with inclusions
It will die
Inheriting mutant huntingtin is a ___
Gain of negative function
Mutant huntingtin can interfere with ___
Normal cellular processes
Activate cell death (apoptosis)
Induce excitotoxicity
Neurodegeneration
Inheriting mutant huntingtin means loosing the function of ____
Normal huntingtin protein
Normal huntingtin mechanisms
Binds to transcription factor called REST and prevents it from entering the nucleus
Mutant huntingtin mechanisms
Fails to bind or has weaker binding to REST. So rest enters the cell and blocks transcription of BDNF
BDNF function
Necessary for neuronal growth and survival
Loss of BDNF
Leads to neuronal death
Pathologic mechanisms by which mutant huntingtin can cause neuronal death
Excitotoxicity mitochondrial dysfunction caspase activation apoptosis nuclear localization aggregation synaptic dysfunction autophagy transcriptional dysregulation proteasomal dysfunction calcium homeostasis
