Role of TDP-43 in post-transcriptional regulation: implications for neurodegeneration and plasticity processes

LUCHELLI L; MULLER IGAZ L

Huerta grande

Congreso; Congreso Argentino de Neurociencias; 2013

Sociedad Argentina de neurociencias

TDP-43 protein has been identified as the main proteic component of the intracellular ubiquitinated inclusions in most cases of Amyotrophic Lateral Sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative processes that are encompassed by the term "TDP-43 proteinopathies". We are studying in vivo the intrinsic properties and physiological role of TDP-43 to define its involvement in neurodegenerative disease. Consequently, we propose to study in vivo TDP-43/mRNA and TDP-43/protein interactions in brain tissue from wild-type mice, with special emphasis on those genes involved in neuronal plasticity and survival. To do this, we are applying different techniques including single and double immunofluorescence, co-immunoprecipitation, immunoblotting, RT-PCR and subcellular fractionation by gradient centrifugation. To investigate the physiological role of TDP-43 and the contribution of TDP-43 in maintaining transcript and protein levels, we are using an antisense oligonucleotide (ASO) approach to stereotaxically infuse TDP-43 or control ASOs for region-specific knock-down of the protein. These studies will provide relevant information to understand the physiological functions of TDP-43 and the molecular mechanisms involved in the pathogenesis of TDP-43 proteinopathies and related neurodegenerative diseases, which in turn may provide the basis for new therapeutic approaches.