Huntington"s disease (HD), is a progressive neurodegenerative disorder in which the defective HD gene contains an unstable expansion of the CAG repeats in its coding region. This mutation leads to the translation of expanded polyglutamine (poly Q) stretches in the N-terminal part of the huntingtin protein. CAG repeat motifs are found in a variety of mRNAs. Expansion of these repeats is a common pathogenic mechanism in so called trinucleotide repeat expansion disorders (TREDs). During this

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... a novel mechanism specifically regulating the translation of CAG repeat containing mRNAs by the MID1 protein complex as a control unit has been identified. The MID1 protein is a microtubule-associated ubiquitin ligase, which binds to the 4 regulatory subunit of PP2A and thereby controls its activity. Additionally, PP2A and its regulatory subunit, α4, integrate the MID1 complex into the mTOR pathway, one of the main translation regulatory pathways. Within the frame of this work it has been shown, that the MID1 protein complex, which is dysfunctional in patients with a midline malformation disorder Opitz BBB/G syndrome (OS), binds to RNA structures containing CAG repeats. It has been demonstrated, that amplification of CAG repeats in huntingtin exon1 mRNAs led to increased binding to the MID1 ribonucleoprotein (RNP) complex and that the protein synthesis directed by CAG repeat containing mRNAs increases with the amount of repeats. Moreover, knockdown of essential components of the MID1 protein complex resulted in a significant reduction of protein produced from the CAG repeat containing mRNAs. It has also been established, that the significant reduction in huntingtin protein aggregates amount seen after interference with the MID1 protein complex was not influenced by proteasome or autophagy degradation processes. Taken together the data presented in this thesis, suggest that CAG repeats in mRNAs are critical for the regulation of huntingtin protein translation. Furthermore, they suggest that the MID1 complex might be a nov [...]