Neurodegenerative diseases and neuronal plasticity: towards new therapeutic strategies in TDP-43 proteinopathies using murine preclinical models.

VASSALLU, M. FLORENCIA; IGAZ, LIONEL M.

Congreso; XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2021

Sociedad Argentina de Investigación en Neurociencias (SAN)

Maintenanceof proper protein homeostasis is an essential activity of mammalian cells.Alterations at the level of RNA binding proteins (RBPs) have recently beendescribed as a central event in many pathologies and often play a central rolein neurodegenerative (ND) diseases. One of the main RBPs involved in theseprocesses is TDP-43, particularly in the ND pathologies Amyotrophic LateralSclerosis (ALS) and Frontotemporal Dementia (FTD). Our general objective is tostudy whether changes in neuronal activation and plasticity play a role inTDP-43-mediated pathogenesis using a murine model of proteinopathies. Inparticular, we will use transgenic mice that conditionally overexpress a mutatedcytoplasmic form (TDP-43-ΔNLS) of human TDP-43 in forebrain neurons in orderto: a) establish the impact of local/global changes in neuronal activation and plasticityin the behavioral deficits mediated by alterations in TDP-43; and b) determine ifthe pharmacological modulation of the BDNF/TrkB pathway (which regulatesneuronal activity/plasticity) using the drug LM22A-4 has therapeutic potentialin our preclinical ALS/FTD model. Using approaches at biochemical,pharmacological and behavioral levels, we aim to analyze the pathophysiologicalroles of TDP-43. The results of this project will allow us to shed light on thepathogenic mechanisms underlying TDP-43 proteinopathies, which in turn will bevital to development new and more effective therapies targeting this group ofdiseases.