In Trieste the Molecular Pathology Group (Buratti) investigates aberrant pre-mRNA processing defects that lead to neurodegeneration. In particular, it studies the biological properties of TDP43, a nuclear factor involved in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). The Neurobiology Group (Feiguin) uses the fruitfly, Drosophila melanogaster, as a model organism that has remarkable genetic conservation with humans, to study some of the most common neurological disorders, including Alzheimer’s and motor neuron diseases.
In 2019 several exciting discoveries were been obtained in ALS and FTLD pathologies. The Molecular Pathology and Neurobiology labs are collaborating on a project funded by the Italian ALS Association (AriSLA) on the identification of cellular transcripts whose expression is affected by changes in TDP- 43 expression, but also by other RNA binding proteins that can rescue or worsen TDP-43 toxicity in flies (Appocher et al., 2017, NAR, 45:8026-8045). Knock-outs were constructed of these toxicity modifier factors in neuronal cell lines and transcriptomic approaches (RNAseq) indentified key transcripts that are currentlybeingvalidated. TheMolecularPathologylabhas,forthefirsttime,shownthatphosphorylation of TDP-43 S375 residue can disrupt its intermolecular interactions (Newell et al., 2018, Brain Pathol. 29:397- 413). A phospho-specific antibody was developed and observed to differentially stain pathological TDP-43 aggregates in the brain of FTLD patients. This result supports recent evidence pointing to the existence in patience of different morphological aggregates whose pathogenicity and importance for disease are still unknown. In 2019 the Molecular Pathology Group commenced investigation of a novel RNA binding protein, RGNEF, which has been hypothesized to represent a novel ALS gene. This research is being performed with several Canadian/American Groups and is supported by the Temerty Foundation (Canada).ical diseases.