Lecture 24: Huntington's Disease Flashcards

1
Q

What is Huntington’s Disease?

A

A rare autosomal dominant progressive neurological disease that causes degeneration of nerve cells in the brain and is inherited from either parent.

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2
Q

What is the average age of onset?

A

symptoms tend to appear when individual is 35 to 40 years of age.

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3
Q

What are HD deaths due to?

A

Due to infection, cardiac causes, falls, and suicide caused from depression.

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4
Q

How does HD affect the brain?

A

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.

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5
Q

HD is caused by an ____ within a single gene

A

expanded trinucleotide repeat

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6
Q

What is the sequence repeated in HD and where is it located ?

A

CAG is the sequence repeated on chromosome 4.

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7
Q

How does the CAG repeats affect individuals with HD?

A

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.

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8
Q

What is the number of repeats where an individual will definitely have HD?

A

> 40

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9
Q

How is HD diagnosed?

A

-based on motor findings: chorea
-cognitive, behavioral, psychiatric and personality changes often precede motor symptoms
-blood test for mutated gene

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10
Q

List some of HD’s symptoms

A

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

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11
Q

Having HD is like having which diseases simultaneously?

A

ALS, Parkinson’s, and Alzheimer’s

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12
Q

Are there any current disease modifying treatments?

A

NO, there are only treatments for the symptoms of HD.

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13
Q

What are two examples of using stem cells to identify potential therapies for HD?

A

-mechanism based approach
—basic research beginning in 2000
-therapeutic based approach
—-neural stem cell transplantation

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14
Q

What is SUMO?

A

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.

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15
Q

What is the name of the SUMO modified protein of HD?

A

HTT

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16
Q

___ enriches SUMO modification of HTT

A

PIAS1

17
Q

__ ___ improves motor activity

A

Decreased PIAS1

18
Q

PIAS1 variant is associated with what?

A

late onset of HD

19
Q

How did it discovered that decreased PIAS1 improves motor activity?

A

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.

20
Q

PIAS1 KD in HD mice show ___

A

synaptic benefit

21
Q

PIAS1 reduction prevents ultrastructural ___ in human ___ of aggregate flakes

A

abnormalities, neurons

22
Q

What are some potential paths for therapeutics?

A

-allele specific oligonucleotides
-viral delivery/ gene therapy
-small molecules

23
Q

True or False: HD is a monogenic disease.

A

True

24
Q

What is the principal neuronal cell type present in the striatum?

A

medium spiny projection neurons

25
Q

What did implanting GMP grade hNSCs into striatum of HD model mice show?

A

It showed a pocket of cells that formed rather than spreading

26
Q

What did ESI-017 hNSC trials in HD mice do ?

A

reduced levels of aggregated HD protein

27
Q

Implanted ESI-017 hNSCs express __

A

BDNF

28
Q

ESI-017 hNSCs express __ ___

A

neuronal markers

29
Q

Some implanted hNSCs differentiate into neurons with _ _ characteristics

A

medium spiny

30
Q

Mouse host cells appear to form __ ___ with implanted hNSCs

A

synaptic connections