All the learning material of part 3 from the elective seminar Translational neuroscience (year 3, Biomedical Sciences/Medicine) summarized using the learning objectives and concepts and explained with illustrations. Contains all information from lectures, self study, working groups and practicals.
SUMMARY MINOR TRANSLATIONAL
NEUROSCIENCE PART 3
Elective minor year 3 – Biomedical Sciences
Radboud University, Nijmegen
Made by: Georgia Graat
,Animal models in neurological diseases
Animal models are commonly used to study diseases. These animal models need to represent the
disease as in humans as well as possible to study treatments and the pathology correctly. A good
disease model is necessary due to ethical aspects, unknown side effects of treatments, unclear
biomarker use and unclear insight into the disease pathology. There are two criteria describing
characteristics of a good disease model:
1. Primary criterion = a perfect disease model recapitulates the molecular mechanisms
underlying the human disease (the complete molecular pathogenesis)
a. The problem is that the exact mechanism behind the disease is often not known yet
and cannot be seen in animals therefore. It has to be studied in animals, then
checked in patients, and back to being checked in animals.
2. Surrogate criteria = (1) it recapitulates the key disease features and (2) it responds to drug
treatments in the same way as human patients.
a. The primary is the most important, but very hard to achieve. The surrogate criteria
are used to generate the best possible models.
Diseases are either sporadic/idiopathic, meaning without a family history, or familial/inherited,
meaning with family history. The latter entails that the disease is caused by a mutation (in a single
gene) that is inherited throughout generations. For many diseases, a fraction of the patients has the
sporadic form and a fraction (often a minority) has a familial form. Mainly in the sporadic form it
remains unclear what the exact onset factor is. There are also some diseases that are completely
genetic. Genetically modified animal models can only be created for familial/inherited forms of
diseases! In other cases (or when the gene is unidentified), environmental toxins are used to create
animal models. However, genetic disease models are much easier to make and usually represent the
disease more accurately.
For familial/inherited diseases, the inheritance pattern
of this monogenic disease can be identified. This
information can be used to correctly provoke the
disease genetically in the animal. In a dominant
pattern, a mutation in one of two gene copies
(heterozygosity) is sufficient to cause the disease. In a
recessive pattern, both gene copies have to be mutant
to cause the disease (homozygosity). Besides this
aspect, there is also the difference between autosomal
and X-linked inheritance. X-linked is harder to detect in
a pedigree and usually has more males affected.
The nature of the mutation entails what type of change has happened in the genome. This can be
one or multiple genes, one or multiple nucleotides or one or multiple proteins. Usually more of a
gene leads to more protein and other mutations cause no function, no production or bad production
of the protein. The type of effect is also caused by the location of the mutation in the genome. This
is determined by the coding and non-coding region as well as where in that region (beginning, middle
or end).
- Missense mutation = a mutation in the coding region of a gene that results in the exchange
of one amino acid by another one
Made by: Georgia Graat
, - Nonsense mutation = a mutation in the coding region of a gene that results in the creation of
a stop codon (results in decay of mRNA or really small protein)
- Frameshift mutation = when nucleotides are inserted or deleted in the coding region of a
gene, resulting in a shift in the reading frame and thus other amino acids
- In-frame deletion = small or large deletion of nucleotides
- In-frame insertion = one or more additional amino acids
- Splice site mutation = results in intron retention or altered inclusion/exclusion of an exon
- Duplication = one or more genes are repeated
- Nucleotide repeat expansion = one or more nucleotides are duplicated
The nature of the mutation has an influence on the effect of the mutation on the protein function.
There are two main effects of changes in the genome. The problem for animal models is that this
part is usually not known and has to be discovered still.
1. Loss of function
a. Full loss of function (amorph) → full disruption or no protein at all
b. Partial loss of function (hypomorph) → reduction of function
i. Haploinsufficiency → one gene that has to make all the protein is not
enough, for dominantly inherited diseases
ii. Dominant-negative function (antimorph) →
good and bad protein form dimers so the
negative gene is dominant
2. Gain of function
a. Gain of wild type function (hypermorph) → more protein
b. Gain of toxic function (neomorph) → novel function that interacts with other
proteins and is harmful for the body
When selecting the genetic strategy that will be used to produce the animal model for a certain
disease, certain parameters have to be considered. The above parameters together determine the
best strategy to induce the disease. When following the steps, you can choose the genetic strategy
that will generate the most functional disease model.
- Inheritance pattern
o Dominant or recessive
o Autosomal versus X-linked
- Location of the mutation
o In coding region
o In regulatory region (promotor or intron or splice site)
- Nature of mutation
- Effect of disease mutation on protein function
o Loss of function
▪ Full loss
▪ Partial loss
o Gain of function
▪ Wild type
▪ Toxic
There are four genetic strategies to choose from when generating an animal disease model. These
are all used in different scenarios as they result in various protein changes.
Made by: Georgia Graat
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