Translational Neuroscience (MED-MIN16 )Translational neuroscience summary of all lectures. Great for people who struggle with big chunks of text. Lots of pictures and bullet points.
Translational Neuroscience
Defining translational models
Primary criterion for a good disease model
A perfect disease model recapitulates the molecular mechanisms underlying the human disease
(= molecular pathogenesis)
Surrogate criteria
• It recapitulates the key disease features
• It responds to (drug) treatments in the same way as human patients
Sporadic/idiopathic: no family history
Familial/inherited: caused by a mutation in a single gene
• for many diseases, a fraction of patients has a sporadic form, and a fraction has a familial
form (often the minority) sporadic/idiopathic: no family history familial/inherited: caused
by a mutation in a single gene Disease e.g. Alzheimer’s disease, Parkinson’s disease, ALS
• some diseases are all genetic/familial e.g. Charcot-Marie-Tooth disease, Huntington’s
disease
only for familial/inherited forms of disease, genetically modified animal models can be created.
Inheritance pattern
• Recessive
• Dominant
• X-linked vs Autosomal
Types of mutations
• missense mutation: a mutation in the coding region of a gene that results in the exchange
of one amino acid by another one
• nonsense mutation: a mutation in the coding region of a gene that results in the creation of
a stop codon → production of a truncated protein or nonsense-mediated mRNA decay
• frameshift mutation: when nucleotides are inserted or deleted in the coding region of a
gene, resulting in a shift in the reading frame
• in-frame deletion: small vs large deletion
• in-frame insertion: → one or more additional amino acids
• splice site mutation: results in intron retention or altered inclusion/exclusion of an exon.
• duplication: of one or more genes
• nucleotide repeat expansion
Effect of mutation on protein function
• loss-of-function
o full loss-of-function (amorph)
o partial loss-of-function (hypomorph)
▪ special cases: haploinsufficiency
▪ dominant-negative function (antimorph)
• gain-of-function
o gain of wild type function (hypermorph)
o gain of toxic function (neomorph)
, Genetic strategies for generating an animal disease model
• knock-in (KI) model: introduction of disease-causing mutations in the orthologous gene
• knock-out (KO) model: inactivation of the orthologous disease gene
o full body knock-out
o ‘conditional’ knock-out (tissue-specific & temporal control)
• knock-down (KD) model: using transgenic RNAi, resulting in partial loss of function
• overexpression (OE) model: overexpression of the disease gene, typically with disease
mutations
o cDNA transgene
o genomic transgene
o duplication (e.g. BAC transgene)
Which parameters to consider for selection of a genetic strategy?
1. Inheritance pattern
2. location of the mutation
• in coding region
• in regulatory region (e.g. promoter, intron)
3. nature of the mutation
4. effect of disease mutation on protein function
Which genetic strategy when? Master Table
inheritance nature of mutation effect of mutation likelihood genetic strategy
pattern
Recessive *nonsense mutation (close to N-terminus) full loss of function *full body KO
*frameshift mutation (close to N-terminus) *tissue-specific
*deletion of a large part or complete ORF KO *(KI model)
*splice-site mutation
*nonsense mutation (close to C-terminus)
*frameshift mutation (close to C-terminus)
*deletion of one or a few critical amino
acids
*missense mutation of a critical amino acid
*insertion of one or a few amino acids in
critical part of the protein
*nucleotide repeat expansion in gene
promotor
*missense mutation partial loss of function *KI model
*deletion of one or a few amino acids *KD model
*insertion of one or a few amino acids (tissue-specific)
*splice-site mutation
*mutation in regulatory region
*nonsense mutation (close to C-terminus)
*frameshift mutation (close to C-terminus)
gain of wild type *KI model
missense mutation function unlikely *OE model
gain of toxic function (tissue-specific)
, inheritance nature of mutation effect of mutation likelihood genetic strategy
pattern
Dominant *same as full loss of function full loss of function *heterozygous KO
unlikely
*nucleotide repeat expansion (→haploinsufficiency) *heterozygous KI
*same as partial loss of function partial loss of function *heterozygous KI
unlikely
*nucleotide repeat expansion
*duplication gain of wild type *OE model
*mutation in regulatory region function *(KI model)
*missense mutation
*missense mutation gain of toxic function *OE model
*nucleotide repeat expansion *KI model
*insertion
*frameshift mutation
*splice site mutation
*mutation altering subcellular localization
(e.g. nonsense mutation close to C-term)
same as gain of toxic function, but only if dominant negative *OE model
the protein functions in a unlikely *KI model
multimer/complex
Pros & cons of different genetic strategies
Genetic strategy Pros Cons
knock-in *identical genetic situation as in patients *technically challenging and time consuming
*no need to know the effect of the *risk of no phenotype e.g. adult-onset
disease mutation on protein function neurodegenerative diseases; human/primate-
upfront specific function of disease protein
*whole body mutant (but can be made
conditional)
knock-out *you will learn about the physiological *only good model if disease is caused by full
function of the disease gene loss of gene function (note: haplo-insufficiency)
*may be technically easier to generate *risk of no phenotype or embryonic lethality
than KI, but still challenging
*can be rendered cell-type/tissue
specific
knock-down *not full loss of function, thus suited to *level of knock-down?
model partial loss of function *potential off-target effects
*technically easier to generate than
KI/KO
*can be cell-type/tissue specific or
ubiquitous
overexpression *relatively easy to generate *transgene expression levels?
*human disease protein can be *phenotypes induced by overexpression or by
expressed the presence of the disease mutation? → need
*can be cell-type/tissue specific or to generate control animal expressing the wild
ubiquitous type disease protein at similar levels
*only suited to model gain of function or
dominant negative disease mechanisms
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