Genetic animal models of neurological disorders –focus on Parkinsons disease

Question 1

What is an animal model?

Answer 1

A living organism in which one or more aspects of human disease or drug action can be investigated. The observed phenomena should resemble that in humans.

Question 2

How is an animal model of disease induced?

Answer 2

a) Through a procedure (e.g., restraint stress, or chemical treatment)
b) Injury (e.g., head trauma)
c) Genetic modification (e.g., manipulating certain genes implicated in a familial form of the disease)

Question 3

Why are animal models needed? (5 reasons)

Answer 3

a) RESEARCH. Access to samples that can’t be obtained from humans (e.g., brain slices directly after some condition)
b) PATHWAYS. Allows to probe new drug pathways, e.g., through genetic means.
c) TEST. Test novel compounds (e.g., drugs) that target new pathways
d) CLINICAL TRIALS. Extensive animal testing is required for clinical trials.
e) IGNORANCE. We still don’t know how to accurately model complex interactions in the human body in vitro or in computational models.

Question 4

What properties are required from animal models?

Answer 4

A) PREDICTIVE VALIDITY. The model needs to predict drug action, and correctly identify clinically efficient substances.
B) FACE VALIDITY. The model needs to replicate symptoms of the disease, either behaviorally or physiologically.
C) CONSTRUCT VALIDITY. It needs to correctly model the causation of the disease. For example, head trauma -> haemorrhagic stroke.

Question 5

What is a transgenic animal?

Answer 5

• An animal that carries a foreign DNA incorporated into genome.
• The transgene insertion is not controlled

Question 6

What is a genetically targeted & genetically engineered animal?

Answer 6

A) Knock-in
- Gene is inserted at a specific locus
B) Knock-out
- Specific gene is deleted (inactivated) in entire organism
- Can lead to developmental problems

Question 7

What is a genetically engineered animal with inducible transgene expression?

Answer 7

A) Tet-on / Tet-off system

• Expression of transgene is temporarily controlled with Doxycycline
• Requires constant doxycycline administration
• Used to avoid perinatal lethality
• Used to precisely control onset of disease
• Used to control expression levels

Question 8

What is a genetically engineered animal with conditional gene targeting?

Answer 8

• Cre/LoxP system
• Allows for spatial control of a gene
• Gene X is disabled only in a specific location in a mouse

Question 9

How to create a genetic animal PD model (example)?

Answer 9

• Recapitulate mutations found in the human form of PD
• Overexpress pathological proteins (alpha-synuclein)
• Genetically disturb mitochondria or other cellular functions in DA neurons

Question 10

What are some main problems with animal models

Answer 10

1) Creation is not easy (construct, face, and predictive validities)
2) Models with good construct validity do not necessarily recapitulate symptoms of the disease
3) Many animal models only display some aspects of the disorder