Cellular and Molecular Neurobiology
Author: Milagros Ovejero | Email: movejero@immf.uncor.edu
Milagros Ovejero1°, Mariano Bisbal1°, Alfredo Cáceres2°, Agustín Anastasía1°2°
1° Instituto Ferreyra (INIMEC-CONICET-UNC)
2° IUCBC (Instituto Universitario de Ciencias Biomedicas de Cordoba)
Alterations in intracellular trafficking have been described as a common feature of several neurodegenerative diseases. In Parkinson’s disease and synucleinopathies, a major pathogenic factor is the accumulation of alpha synuclein (AS). Although the mechanisms by which this protein causes neurodegeneration are not clearly understood, there are several hypotheses that includes that AS may cause defects in intracellular trafficking. In this study, we synchronized the exocytic pathway in mammalian hippocampal neurons to investigate whether AS impacts protein trafficking. Our results clearly demonstrate that AS induces selective trafficking deficits in different proteins; specifically we analyzed p75 neurotrophin receptor (p75NTR) and transferrin receptor (TfR). AS disrupts p75NTR trafficking while TfR remains unaffected. Moreover, AS causes defects in p75NTR vesicle fission leading to a decrease in the size of vesicles transporting this receptor. These experiments were performed using both confocal and STED nanoscopy. The underlying mechanism appears to involve abnormal stabilization of the actin cytoskeleton, which alters Golgi apparatus fission and consequently vesicle structure. Notably, we managed to rescue the observed effects on trafficking and vesicle morphology using an active Cofilin. This research provides new insights into the mechanisms by which AS contributes to neurodegeneration, advancing our understanding of Parkinson’s disease and synucleinopathies.