V-086 | A C. elegans Model for Studying the Functional Impact of the neurodegeneration-related protein TDP-43

Disorders of the Nervous System
Author: Ailin Lacour | Email: ailin.lacour@gmail.com

Ailin Lacour^1°2°, Florencia Vassallu^3°4°,Diego Rayes^1°2°, Lionel Muller Igaz^3°4°

^1° Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB)-CONICET, Bahía Blanca, Argentina
^2° Universidad Nacional Del Sur (UNS). Departamento de Biología, Bioquímica y Farmacia, Bahía Blanca, Argentina
^3° Universidad de Buenos Aires, Facultad de Ciencias Médicas. Departamento de Ciencias Fisiológicas. Buenos Aires, Argentina
^4° CONICET – Universidad de Buenos Aires. Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay). Buenos Aires, Argentina

TDP-43 proteinopathies are characterized by the pathological accumulation of TDP-43 in the cytoplasm, leading to neuronal dysfunction and degeneration. To study the effects of cytoplasmic TDP-43 accumulation, we generated C. elegans models overexpressing either wild-type (WT) human TDP-43 (hTDP-43, nuclear) or a cytoplasmic form with a mutated nuclear localization signal (ΔNLS). Both forms were specifically expressed in serotonergic neurons, which in C. elegans modulate behaviors related to food, such as pharyngeal pumping, egg-laying, and locomotion upon encountering food. Our results show that in young adult animals, both TDP-43 transgenic strains exhibit significant defects in these behaviors compared to WT animals, though less severe than those observed in tph-1 mutants, which cannot synthesize serotonin (tph-1 > ΔNLS > hTDP-43 > WT). Despite these phenotypic defects, fluorescence imaging revealed that the morphology of the serotoninergic neurons was unaffected. Notably, fluoxetine, a serotonin reuptake inhibitor, partially rescued the defects in TDP-43-expressing animals, indicating that serotonin release was not completely disrupted. These findings suggest that TDP-43 mislocalization leads to early functional impairments before morphological changes occur. We have established a C. elegans model to study cytoplasmic TDP-43 aggregation, providing a valuable tool to explore the underlying mechanisms of TDP-43 proteinopathies and to screen potential therapeutic agents.