Integrated approaches to study translational defects in neurodegenerative diseases and bacterial infections

The cellular process of protein synthesis, or translation, is the most energy consuming process in cells. It represents the core mechanism to regulate protein abundance and controls a variety of physiological cellular processes: cell growth, development, host-pathogen interactions and immune response, response to injury, local protein synthesis in neurons, memory formation and synaptic plasticity. Hence, it is not surprising that mRNAs are mainly controlled at the translational rather than transcriptional level. In fact, when post-transcriptional and translational controls are lost, important pathologies such as cancer, autism, and neurodegeneration emerge, pinpointing the importance of their contribution in disease development. The cytoplasmic machinery where these processes take place is the polysome, critical translation hubs where different layers of mRNA control converge, giving rise to intimate relationships between protein synthesis, mRNA decay, ubiquitination and protein unfolding response. In this context we explore the hypothesis that translation plays a pivotal role in the pathogenesis of Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis. Combining cutting-edge mRNA positional sequencing, rRNA epitranscriptomics, proteomics, and 3D ultrastructural cryo-EM and AFM, our work aims at systematically detailing the translational defects in these devastating diseases.

Fund(s): 2021-2024 AFM Telethon (France) 2020-2024 H2020-MSCA-ITN-2020 (EU) 2019-2022 Telethon (Italy) 2019-2020 AFM Telethon (France) 2018- 2021 ARISLA (Italy) 2017-2018 ALS Association (USA) 2013-2017 Autonomous Province Trento (Italy)

Members:
Mauro Dalla Serra
Lorenzo Lunelli
Gabriella Viero (Principal investigator)