Tau Gene Mutation for Human-Like Isoform Expression in Disease Models
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Solution Overview
Problem
Current disease model animals for tauopathies do not accurately replicate the expression pattern of tau protein isoforms in the adult human brain, where approximately equal amounts of 3R and 4R tau types are expressed, limiting their effectiveness in mimicking human clinical conditions.
Innovation Solution
A method involving the production of animals carrying a mutation in the tau gene that fails to express the tenth exon, using genome editing technologies, to create a disease model that accurately expresses both 3R and 4R tau isoforms, allowing for the injection of tau seeds derived from human patients to induce pathological tau fibril deposition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional disease model animals are used, then the model can be established, but the expression pattern of tau protein isoforms does not accurately replicate human brain conditions
Solution Approach 1:
The patent applies parameter changes by modifying the tau gene to control alternative splicing of the tenth exon. By introducing specific mutations (such as deleting the tenth exon or mutating splice sites), the model animals express tau isoforms in proportions that replicate human brain patterns (approximately equal amounts of 3R and 4R tau types), resolving the contradiction between model reliability and construction complexity.
2Reliability
If the tenth exon is expressed, then 4R tau type is produced, but the model cannot accurately represent human brain isoform distribution
Solution Approach 1:
The patent applies local quality by making targeted modifications specifically at the tenth exon region of the tau gene. Instead of altering the entire gene, the invention focuses on localized changes (deleting the tenth exon or mutating its splice sites) to control alternative splicing, thereby achieving human-like tau isoform distribution while maintaining relative simplicity in gene modification procedures.
3Manufacturing precision
If genome editing is used to create the model, then accurate tau isoform expression is achieved, but the production process becomes more complex
Solution Approach 1:
The patent applies preliminary action by designing and introducing specific genetic modifications (such as deleting the tenth exon or mutating splice donor/acceptor sites) into the animal model before tau protein expression occurs. This pre-established genetic configuration ensures that the animals naturally express tau isoforms in human-like proportions, achieving manufacturing precision in isoform expression while streamlining the overall process by avoiding complex postnatal manipulation.
Data Source
AI summary
The present invention provides a disease model animal for tauopathies which reproduces the expression pattern of tau protein isoforms of adult human brain, that is, approximately equal amounts of 3R type tau and 4R type tau being expressed in the adult brain. The method for producing the disease model animal for tauopathies of the present invention comprises the steps of: preparing a tau seeds; and injecting the tau seeds in the brain of an animal carrying a mutation in the tau gene which fails to express the tenth exon. The animal carrying a mutation in the tau gene which fails to express the tenth exon may be produced by using any of the genome editing, gene targeting or base editing technologies.