Mura, Maria Elena (2012) Molecular mechanism involved in Amyotrophic Lateral Sclerosis: role of Bcl2-A1 and TDP-43 genes in motor neuron degeneration. Doctoral Thesis.
Expression of mutant SOD1 typical of familial amyotrophic lateral sclerosis (ALS) induces the expression of Bcl2-A1specifically in motor neurons of transgenic mice. In this work, I have used NSC-34 cells and transgenic mice expressing mutant SOD1 to unravel the molecular mechanisms and the biological meaning of this up-regulation. I report that up-regulation of Bcl2-A1 by mutant SOD1 is mediated by activation of the redox sensitive transcription factor AP1 and that Bcl2-A1 interacts with pro-caspase-3 via its C-terminal helix α9, inhibiting pro-caspase-3 activation in NSC-34 expressing mutant SOD1. The discovery of the relationship between ALS and TDP-43 mutations has determined the interest in role of TDP-43 in neurodegeneration. TDP-43, a DNA/RNA binding protein, serves multiple functions: transcriptional regulation, pre-mRNA splicing and translational regulation. It is the major component of the ubiquitinated inclusions seen not just in ALS. It is unsettled if TDP-43 mutants provoke disease from a loss of function or gain of toxicity or both, but TDP-43 misaccumulation seems central for the pathogenesis. In this work I have investigated the role of three TDP-43 mutations, using SH-SY5Y cells. I report that these mutations determine a partial redistribution of the protein, but in SH-SY5Y cells I did not observe protein aggregation. These data provide new insights on the molecular mechanisms leading to ALS disease and provide new targets to prevent motor neuronal death.
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