Time:
14:30
Location:
Conference Hall, Building C, Area Science Park, Padriciano 99, Trieste
Speaker:
Annalisa Pastore, UK Dementia Research Institute (Maurice Wohl Institute of King’s College London), European Synchrotron Radiation Facility – Grenoble
Abstract:
Neurodegenerative diseases comprise a large family of pathologies some time, but not always, related to ageing. In my seminar, I will give examples of how structural biology can help understanding the mechanisms linked to neurodegeneration, focusing on amyotrophic lateral sclerosis (ALS), an incurable and lethal motor neuron disease. I am going to discuss the role of RNA in protein aggregation demonstrating a direct effect of RNA binding as a cause of the aggregation of RNA-binding proteins. We used this knowledge to study the effects of in silico-designed RNA aptamers on the aggregation of TDP-43, one of the main players in ALS. We showed that high affinity binding RNA aptamers are able to interfere with TDP-43 aggregation as a function of their nucleotide composition, binding affinity, and length in vitro. The effect is sequence specific since aptamers that share compositional and sequence similarities with natural partners and that have a high affinity for the protein, have a strong inhibitory effect against aggregation already at equimolar protein:RNA ratio. Conversely, non-UG-rich RNA sequences that have low affinity have no effects or induce faster aggregation. These important results have laid the ground towards understanding the mechanisms which determines ALS-related pathologies and offer a hope for disease treatment.