Periodic Reporting for period 1 - Prot-RAN (What drives the RAN translation and why do we get neurodegenerative disease when it goes wrong?)
Periodo di rendicontazione: 2020-07-01 al 2022-06-30
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.
During this work, I supervised two Master Students (one thesis defended in 2021, another one ongoing project started in December 2022) and one Bachelor (ongoing project started in December 2022). I also received a Sonata research grant for young investigators from National Science Centre (Poland), which enables me to pursue my research on RAN translation after the end of MSCA fellowship and to co-supervise one PhD student.
I have received training in RNA biology and microscopy (via collaboration during project in Host lab), attended a series of on-site courses on student supervision and research management (organized by the Host Institution). I also collaborated with researchers from AMU Faculty of Chemistry to develop a MS-based quantitative analysis of FMRpolyG and other RAN proteins.
The scientific background of our project was described in 1 review paper, and results of our research will be reported in 3 papers (two manuscripts in preparation, one need more supporting data). This work has been presented at two conferences (one poster, one talk), and popularized during AMU Biology Night, workshop organized for PhD students in Polish Academy of Sciences, Poznan and visit in pre-school class. Our activities were posted at Web (https://annbau1-protran.web.amu.edu.pl/) Twitter (@UAM_IBMiB) and LinkedIn (my personal account).
The results were disseminated during international conferences, and will be published as open access articles in peer-reviewed journals. Additionally, after publication, the mass spectrometry data will be shared in the open-access servers to enable other scientists to perform their in-silico analysis.
What is more, the presentation of our MSCA project during Biology Night and workshop for PhD students helped to increase awareness about FXTAS and R AN translation in society.