Projektbeschreibung
Die Rolle der RAN-Translation bei der Neurodegeneration
Das fragile X-assoziierte Tremor-/Ataxie-Syndrom (FXTAS) ist eine erbliche neurodegenerative Erkrankung, die durch eine Expansion von CGG-Repeats in der nicht codierenden Region des Fragile-X-Mental-Retardation-1-Gens (FMR1-Gens) verursacht wird. Neue Erkenntnisse deuten darauf hin, dass die Repeat-assoziierte durch Nicht-AUG-Startcodons initiierte Translation (RAN-Translation) an der Pathogenese des FXTAS beteiligt ist, indem dabei toxische Proteinprodukte produziert werden, die in Nervenzellen akkumulieren und zum Tod führen. Ziel des EU-finanzierten Projekts Prot-RAN ist es, mithilfe modernster Technologien die an der Initiierung und Verlängerung der RAN-Translation beteiligten Proteine zu identifizieren. Die Arbeit wird einen ganzheitlicheren Überblick über die RAN-Translation liefern und mögliche therapeutische Ziele für durch Repeat-Expansion verursachte Erkrankungen wie FXTAS, Chorea Huntington, spinozerebelläre Ataxien oder myotone Dystrophie identifizieren.
Ziel
The short tandem repeats are common in human genome, but their uncontrolled expansions may lead to several inherited disorders. In Prot-RAN project, I will focus on the expansion of trinucleotide CGG repeats (CGGexp) in the 5’UTR of fragile X mental retardation 1 (FMR1) gene, which causes common neurodegenerative disease, known as fragile X-associated tremor/ataxia syndrome (FXTAS). The pathogenesis of FXTAS remains unclear, and one of the possible mechanisms, the repeat associated non-AUG initiated (RAN) translation, can be shared in majority of microsatellite expansion diseases, as it was already linked to 9 different disorders. In FXTAS, the CGGexp enhances RAN translation from the 5’UTR of FMR1 mRNA, what leads to the production of toxic polyglycine or polyalanine containing proteins. These aberrant products accumulate in nuclear inclusions in the brain of FXTAS patients, impairing the nuclear lamina architecture and leading to neuronal death. The RAN translation mechanism is still not well understood; therefore, in the proposed project I will identify and investigate the role of proteins implicated in RAN translation initiation/elongation. To achieve this goal, I will benefit from the synergy between my long-time experience in mass spectrometry and the expertise of the host lab in RNA biology, and I will bridge cutting-edge proteomics with RNA biology techniques. Briefly, I will employ the CGGexp RNA-targeting pull-down approaches combined with proteomic profiling, RNA mutagenesis, high throughput protein expression analysis and RNA/protein interaction studies in a context of their functional implications. The role of identified proteins will be then verified in other expansion disorders, e.g. Huntington’s disease, giving insight into more global view of the RAN translation. As a result, the discovered factors driving RAN translation and knowledge of mechanism of their action could be used as potential new targets for therapeutic strategies.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenUnterauftrag
H2020-WF-02-2019
Finanzierungsplan
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
61 712 POZNAN
Polen