PRO-MINE :: Background
Nuclear factor TDP-43
Nuclear factor TDP-43 is an example of a protein with high SNP (single nucleotide polymorphism) count. TDP-43 is a multifunctional RNA binding protein that plays a role in several cellular processes such as transcription, pre-mRNA splicing, mRNA stability and mRNA transport. Recently, TDP-43 has also been found as the major protein component of the intracellular inclusions occurring in the neuronal tissues of patients affected by a series of neurodegenerative diseases which include Fronto Temporal Lobar Degeneration (FTLD-U), Amyotrophic Lateral Sclerosis (ALS) and in a significant proportion of Alzheimer disease patients. In affected neurons, TDP-43 is abnormally mislocalized to the cytoplasm, ubiquitinated, hyperphosphorylated, and cleaved to generate C-terminal fragments.
In the beginning, the question was still open regarding the relative importance of this protein: should TDP-43 protein inclusions be considered as a simple pathological curiosity of these diseases or did it really play a role in their origin and progression?. The recent development of several animal models, from simpler organisms to more complex ones, has clearly shown the pathological potential of both TDP-43 depletion and overexpression in general.
Another evidence that TDP-43 misregulation may be the cause of disease has been provided by several genetic findings that have identified TDP-43 mutations in about 5% of the patients, as recently reviewed by Pesiridis et al..
With only two exceptions (p.Ala90Val and p.Asp169Gly) all the disease associated mutations in human TDP-43 are all localized in the C-terminal tail of the protein (a region that in hnRNP proteins is usually associated with protein-protein interactions) and are all except p.Tyr374X characterized as missense mutations (see figure below).
In this respect, it is important to note that all these mutations are dominant traits and, until today, in the C-terminal tail no missense mutation has been found in healthy controls. At the moment, very little is known about the role potentially played by these mutations. Nonetheless, expression of mutant forms of this protein in mice, rat, zebrafish, chicken, yeast and neuronal cell lines can reproduce neurodegenerative effects similar to those observed in human disease.
1) Buratti E, Baralle FE (2009) The molecular links between TDP-43 dysfunction and neurodegeneration. Adv Genet 66: 1-34
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