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What drives the RAN translation and why do we get neurodegenerative disease when it goes wrong?

Project description

The role of RAN translation in neurodegeneration

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disease caused by the expansion of CGG repeats in the non-coding region of the fragile X mental retardation 1 (FMR1) gene. Emerging evidence indicates that repeat associated non-AUG initiated (RAN) translation is implicated in FXTAS pathogenesis by producing toxic protein products that accumulate in neuronal cells, causing death. Scientists of the EU-funded Prot-RAN project aim to identify proteins implicated in RAN translation initiation and elongation using cutting-edge technologies. The work will provide a more global view on RAN translation and unveil potential therapeutic targets for repeat expansion disorders such as FXTAS, Huntington's disease, spinocerebellar ataxias or myotonic dystrophy.

Objective

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.

Call for proposal

H2020-WF-2018-2020

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Sub call

H2020-WF-02-2019

Coordinator

UNIWERSYTET IM. ADAMA MICKIEWICZA W POZNANIU
Net EU contribution
€ 149 625,60
Address
ULICA HENRYKA WIENIAWSKIEGO 1
61 712 POZNAN
Poland

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Region
Makroregion północno-zachodni Wielkopolskie Miasto Poznań
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 149 625,60