Molecular Pathology


Research Interests

RNA-protein interactions. Defective RNA processing and neurodegeneration. Genetic disease caused by defective splicing.

Description of Research

In Trieste, the Molecular Pathology Group investigates aberrant pre-mRNA processing defects that lead to neurodegeneration. Specifically, our Group studies the biological properties of TDP43, a nuclear factor involved in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). The main research area of our lab is to identify cellular transcripts whose expression can be affected by changes in TDP-43 expression but also by other RNA binding proteins that can rescue or worsen TDP-43 toxicity in flies.

Recently, we have performed the knock-out of these toxicity modifier factors in neuronal cell lines and have used transcriptomic approaches (RNAseq) to identify these key transcripts that are currently being validated in neuronal cell lines and in primary rat neurons. A very interesting novel target has been identified as the NOS1AP gene that controls dendritic spine formation in the brain and whose levels are altered in ALS patients.

In addition, our lab has uncovered for the first time that phosphorylation of TDP-43 S375 residue can disrupt its intermolecular interactions and can profoundly affect mitochondrial functioning. These experiments are highlighting the increasing importance of TDP-43 post translational modifications and the role they might play in disease. Finally, starting from 2019 the Molecular Pathology Group has also started to investigate a novel RNA binding protein, called RGNEF, which has been hypothesized to represent a novel ALS gene. This research will be performed together with several Canadian/American groups and is supported by the Temerty Foundation (Canada). In ICGEB, the aims of the study will be to use advanced cellular and transcriptomic approaches to better understand the links between this protein, TDP-43, and neurodegeneration

Recent Publications

NOS1AP is a novel molecular target and critical factor in TDP-43 pathology. Cappelli S. Spalloni A., Feiguin F, Visani G, Šušnjar U, Brown A-L, NYGC ALS Consortium, de Bardi M, Borsellino G, Secrier M, Phatnani H, Romano M, Fratta P, Longone P, and Buratti E. Brain Communications, 2022, in press

Unravelling the toxic effects mediated by the neurodegenerative disease-associated S375G mutation of TDP-43 and its S375E phosphomimetic variant. Paron F., Barattucci S., Cappelli S., Romano M., Berlingieri C., Stuani C., Laurents D., Mompeán M., Buratti E. Journal of Biological Chemistry,2022, 298:102252.

TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. Brown A.L., Wilkins O.G., Keuss M.J., Hill S.E., Zanovello M., Lee W.C., Bampton A., Lee F.C.Y., Masino L., Qi Y.A., Bryce-Smith S., Gatt A., Hallegger M., Fagegaltier D., Phatnani H.; NYGC ALS Consortium, Newcombe J., Gustavsson E.K., Seddighi S., Reyes J.F., Coon S.L., Ramos D., Schiavo G., Fisher E.M.C., Raj T., Secrier M., Lashley T., Ule J., Buratti E., Humphrey J., Ward M.E., Fratta P. Nature, 2022, 603:131-137.

Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43. Garcia Morato J., Hans F., von Zweydorf F., Feederle R., Elsässer S.J., Skodras A.A., Gloeckner C.J., Buratti E., Neumann M., Kahle P.J. Nature Communications, 2022, 13:1223.

Distinguishing post-translational modifications in dominantly inherited FTD: FTLD-TDP Type A (GRN) versus Type B (C9orf72). Cracco L., Doud E.H., Hallinan G.I., Garringer H.J., Jacobsen M.H., Richardson R., Buratti E., Vidal R., Ghetti B., Newell K.L. Neuropathology and Applied Neurobiology 2022:e12836

Cell environment shapes TDP-43 function with implications in neuronal and muscle disease. Šušnjar U., Škrabar N., Brown A.-L., Abbassi Y., Phatnani H, NYGC ALS Consortium, Cortese A., Cereda C., Bugiardini E., Cardani R., Meola G, Ripolone M., Moggio M., Romano M., Secrier M., Fratta P., Buratti E.Communications Biology, 2022, 5:314.