Lecture 24: Huntington's Disease Flashcards
What is Huntington’s Disease?
A rare autosomal dominant progressive neurological disease that causes degeneration of nerve cells in the brain and is inherited from either parent.
What is the average age of onset?
symptoms tend to appear when individual is 35 to 40 years of age.
What are HD deaths due to?
Due to infection, cardiac causes, falls, and suicide caused from depression.
How does HD affect the brain?
The loss of medium spiny neurons in striatum.
-loss of connectivity between the cortex and striatum.
-HD affects the whole brain but certain areas are more vulnerable than others.
HD is caused by an ____ within a single gene
expanded trinucleotide repeat
What is the sequence repeated in HD and where is it located ?
CAG is the sequence repeated on chromosome 4.
How does the CAG repeats affect individuals with HD?
The amount of repeats present on the chromosome correlated to the age of on set.
-the higher the # of repeats the younger symptoms may be present.
What is the number of repeats where an individual will definitely have HD?
> 40
How is HD diagnosed?
-based on motor findings: chorea
-cognitive, behavioral, psychiatric and personality changes often precede motor symptoms
-blood test for mutated gene
List some of HD’s symptoms
Cognitive
-language difficulties
-lack of awareness
-deficits in learning and memory
Motor
-chorea
-impaired speech
-poor balance/risk of falls
Behavioral
-depression
-suicidality
-aggression and psychosis
Having HD is like having which diseases simultaneously?
ALS, Parkinson’s, and Alzheimer’s
Are there any current disease modifying treatments?
NO, there are only treatments for the symptoms of HD.
What are two examples of using stem cells to identify potential therapies for HD?
-mechanism based approach
—basic research beginning in 2000
-therapeutic based approach
—-neural stem cell transplantation
What is SUMO?
SUMO is a protein that can decorate other proteins via a process called SUMOlation that can regulate the toxicity of proteins linked to neurodegenerative diseases.
What is the name of the SUMO modified protein of HD?
HTT
___ enriches SUMO modification of HTT
PIAS1
__ ___ improves motor activity
Decreased PIAS1
PIAS1 variant is associated with what?
late onset of HD
How did it discovered that decreased PIAS1 improves motor activity?
Using a mouse model with untreated HD we saw it had a hard time running down the pole. After using the miPIAS1.3 in the mouse there was an improvement on how fast it went down the pole.
PIAS1 KD in HD mice show ___
synaptic benefit
PIAS1 reduction prevents ultrastructural ___ in human ___ of aggregate flakes
abnormalities, neurons
What are some potential paths for therapeutics?
-allele specific oligonucleotides
-viral delivery/ gene therapy
-small molecules
True or False: HD is a monogenic disease.
True
What is the principal neuronal cell type present in the striatum?
medium spiny projection neurons
What did implanting GMP grade hNSCs into striatum of HD model mice show?
It showed a pocket of cells that formed rather than spreading
What did ESI-017 hNSC trials in HD mice do ?
reduced levels of aggregated HD protein
Implanted ESI-017 hNSCs express __
BDNF
ESI-017 hNSCs express __ ___
neuronal markers
Some implanted hNSCs differentiate into neurons with _ _ characteristics
medium spiny
Mouse host cells appear to form __ ___ with implanted hNSCs
synaptic connections
