The project “Prot-RAN: What drives the RAN translation and why do we get neurodegenerative disease when it goes wrong?” studies the regulation of non-AUG initiated protein translation. This phenomenon is based on the observation that the expanded short tandem repeats in RNA can trigger the production of mutant proteins, without the canonical AUG initiation codon, which is usually used for protein translation. This aberrant RAN translation was initially described in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy (DM1), and to date was linked to many neurodegenerative diseases, e.g. fragile X-associated tremor/ataxia syndrome (FXTAS) or Huntington’s Disease (HD).
The short tandem repeats, usually three to eight base pairs long, are common in human genome. They are also genetically unstable and their uncontrolled expansion may lead to inherited disorders. For example, in the 5’UTR of fragile X mental retardation 1 (FMR1) gene, healthy individuals possess typically between 5 and 54 CGG trinucleotide repeats, while premutation expansions (55-200 CGG repeats) causes FXTAS. Symptoms of FXTAS include intention tremor, gait ataxia, parkinsonism and cognitive decline, amongst others.
The pathogenesis of FXTAS remains unclear, and to date, various pathogenesis models have been proposed. One of the possible mechanism is the repeat associated non-AUG initiated (RAN) translation. Resulting aberrant proteins- FMRpolyG containing polyglycine tracts- accumulate in nuclear inclusions in the brain of FXTAS patients, leading to neuronal death.
Despite emerging reports about the possible mechanisms driving RAN translation, still little is known about this process. The main goal of Prot-RAN project was to identify proteins regulating RAN translation. This is needed to understand the disease mechanisms and find potential drug targets for neurodegenerative disease- FXTAS. In parallel, the other dimension of the MSCA Individual Fellowship was to ensure the transfer of knowledge between the host and the researcher (and vice versa), in order to ensure successful career advancement during the fellowship.
