Advances in Genetics, Volume 91, Friedmann T., Dunlap J.C., Goodwin S.F., 2015

Advances in Genetics, Volume 91, Friedmann T., Dunlap J.C., Goodwin S.F., 2015.
 
   At present, there are very few therapeutic options for patients affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, almost all patients affected by ALS or tau-negative FTD share in their brains the presence of aggregated TDP-43, a nuclear factor that plays an important role in regulating RNA metabolism. For this reason, this protein represents a very promising target to develop novel therapeutic options. Over the years, these options have mostly involved the search for new effectors capable of reducing aberrant aggregation or enhancing its clearance by UPS-dependent protein guality control or autophagy system. Targeting eventual mutations in the seguence of this protein might represent a parallel alternative therapeutic option. To this date, the study of various patient populations has allowed to find more than 50 mutations associated with disease. It is, therefore, important to better understand what the functional conseguences of these mutations are. As discussed in this review, the emerging picture is that most TDP-43 mutations appear to directly relate to specific disease features such as increased aggregation, half-life, or altered cellular localization and protein—protein interactions.




FUNCTIONAL CONSEQUENCES OF TDP-43 MUTATIONS.
From the functional point of view, very few studies have systematically targeted TDP-43 mutations to find their possible effects on protein structure/function. In fact, Figure 1(B), shows that there is actually very little or absolutely no information for more than half of the described mutations (in addition to the simple description of their occurrence in patients). Indeed, less than half of the described mutations have been analyzed with regards to their consequences on cellular metabolism. This situation reflects the fact that most studies have tested disease mutations as additional experiments when characterizing TDP-43 wild-type properties. Consequently, the earliest a mutation appeared in the scientific literature, the greater the chance of being tested for functional consequences. Indeed, Figure 1(B) shows that only four of these mutations have been tested in mice animal models (A315T, Q331K, M337V, and G348C), although this number can be approximately doubled if we consider also Drosophila, Zebrafish, and C. elegans models.

Notwithstanding these drawbacks, Table 1 lists all the functional changes associated with each mutation described in peer-reviewed manuscripts until now. As can be seen from the individual entries in this table, the effects of mutations can include a huge amount of possible consequences: from differences in individual gene expression levels to extensive neurodevelopmental alterations. Such a variety, of course, does not really allow making general considerations.

Contents.
1. Introduction.
2. TARDBP Mutation Spectrum.
3. Clinical Significance of TDP-43 Mutations.
4. Functional Consequences of TDP-43 Mutations.
5. RNA-Specific Therapies for TDP-43 Mutations.
6. Conclusions and Future Perspectives.
Acknowledgments.
References.



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Теги: учебник по биологии :: биология :: Friedmann :: Dunlap :: Goodwin