Role of nuclear factor TDP‐43 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Abstract

TDP‐43 is one of the major components of the neuronal and glial inclusions observed in several neurodegenerative diseases such as ALS and FTLD. These characteristic aggregates are a “landmark” of the disease but their role in the pathogenesis is still obscure. At the moment, in fact, very little is known regarding the biological processes that underlie TDP‐43 aggregation and, most importantly, its potential consequences on cellular metabolism.In our laboratory, aggregate formation has been recently assessed using a novel system capable of inducing TDP‐43 aggregation in experimental cell lines and primary neuronal cultures. Our experiments show that in cell lines and primary rat neuronal cultures the introduction of tandem repeats carrying the 331‐369 Q/N region from TDP‐43 can trigger the formation of phosphorylated and ubiquitinated aggregates that recapitulate many of the characteristics observed in patients (Figure 1A and 1B). We have recently better characterized their formation with regards to: (i) the ability of other regions of TDP‐43 to influence aggregate formation (ii) the composition of the aggregates (iii) the effects of these aggregates on cellular pre‐mRNA splicing regulation (iv) the physiological consequences of inducing these aggregates in Drosophila.In addition, we have recently started to engineer a wide range of Drosophila models to determine which of the major hnRNP proteins can induce neurodegeneration. For the moment, we have already gathered evidence that the interplay between the Drosophila homologues of TDP‐43 and hnRNP A/B can be critical for neurodegeneration. The final aim of this work is to determine how hnRNP proteins can generally contribute positively or negatively to the action of TDP‐43 in mediating neurodegeneration.