Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation.

The overview of TDP 43 functions immediately disclose a number of open questions regarding its pathological role. The formation of TDP-43 aggregates is one of the major distinguishing features of TDP-43 proteinopathies, especially in patients affected by Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar degeneration (FTLD). At the moment, however, very little is known regarding the biological processes that underlie TDP-43 aggregation and, most importantly, its potential consequences on cellular metabolism. For these reasons, it is particularly important to further investigate this process in order to gain a better understanding of the pathology and to develop novel therapeutic effectors. In this report, we focus on a series of missense mutations associated with disease in the 342-366 region of this protein to examine their ability to affect RNA splicing regulation and to induce aggregate formation. In particular, aggregate formation was assessed in a novel system capable of inducing TDP-43 aggregation in experimental cell lines and primary neuronal cultures. The results of this analysis showed that the presence of two of these missense mutations in the 342-366 region (G348V and N352S) could differentially affect the levels and appearance of TDP-43 aggregation with respect to the wild-type protein. This article is part of a Special Issue entitled RNA-Binding Proteins.