New papers from Professor Baralle's lab

Please, have a look at the new papers being in press from Professor Baralle's group:

Borroni, B., Archetti, S., Del Bo, R., Papetti, A., Buratti, E., Bonvicini, C., Agosti, C., Cosseddu, M., Turla, M., Di Lorenzo, D., Comi, G.P., Gennarelli, M., Padovani, A. TARDBP mutations in Frontotemporal Lobar Degeneration: frequency, clinical features, and disease course. 2010. Rejuvenation Res. 13(5), 509-517


Abstract: The 43-kD transactive response (TAR)-DNA-binding protein (TARDBP) mutations have been demonstrated to be causative of sporadic and familial forms of amyotrophic lateral sclerosis. More recently, these mutations have been reported in cases of frontotemporal lobar degeneration (FTLD). The aim of this study was to evaluate the role of TARDBP genetic variations in a large sample of consecutive patients with FTLD. A total of 252 FTLD patients were investigated. Each subject had a clinical and neuropsychological evaluation and a brain imaging study. The clinical diagnosis was confirmed by at least 1 year of follow up. The entire TARDBP gene, the intronic flaking regions, and the 5'-untranslated region (5'-UTR) were screened. Six genetic variations were identified in patients with behavioral variant frontotemporal dementia (FTD) and FTD with motor neuron disease phenotypes. Two of these mutations, namely N267S and M359V, lead to amino acid changes within exon 6. We further identified three genetic variations, i.e., Y214Y, IVS-IV + 45C/T, and 5'-UTR G/A, that could potentially affect the normal splicing process as predicted by in silico analyses. None of these genetic variations was found in healthy age-matched controls. Moreover, we identified a previously described benign variant, A66A, in 5 patients. Our study has confirmed and extended the list of pathogenetic mutations in the TARDBP gene in both apparently sporadic and familial FTLD patients. This work further supports the need for TARDBP screening in FTLD. Also intronic splicing that affects mutations should be considered as well.

Buratti, E., Baralle, F.E. The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation. 2010. RNA Biol. 7(4) (in press)

doi: not yet available

Abstract: Heterogeneous ribonucleoproteins (hnRNPs) are multifunctional RNA-binding proteins (RBPs) involved in many cellular processes. They participate in most gene expression pathways, from DNA replication and repair to mRNA translation. Among this class of proteins, TDP-43 (and more recently FUS/TLS) have received considerable attention due to their involvement in several neurodegenerative diseases. This finding has prompted many research groups to focus on the gene expression pathways that are regulated by these proteins. The results have uncovered a considerable complexity of TDP-43 and FUS/TLS functions due to the many independent mechanisms by which they may act to influence various cellular processes (such as DNA transcription, pre-mRNA splicing, mRNA export/import). The aim of this chapter will be to review especially some of the novel functions that have been uncovered, such as role in miRNA synthesis, regulation of transcript levels, and potential autoregulatory mechanisms in order to provide the basis for further investigations.

Buratti, E., Baralle, D. Novel roles of U1 snRNP in alternative splicing regulation. 2010. RNA Biol. 7(4) (in press)

doi: not yet available

Abstract: Since its discovery in the early days of splicing research, U1snRNP has been recognized as a crucial player in the early stages of the splicing process. In particular, binding of U1snRNP to the 5'splice site of exons is a fundamental step in the formation of the early splicing complex and directs the subsequent assembly of the functional spliceosome. In recent years, the way that the U1snRNP molecular complexes recognize real 5' ss sequences from a huge background of similar decoy sequences has been extensively studied. In this review, we will provide an account of the latest functional properties of U1snRNP as a splicing factor, its role in transcriptional and mRNA degradation processes, and how these properties can be exploited to act as prospective therapeutic or gene silencing strategies. Finally, we will discuss the latest experimental evidence that challenges the absolute requirement of U1snRNP presence for splicing to take place.