Autophagy modulates manganese toxicity in astroglial and microglial cells.

PORTE ALCON SOLEDAD*; GOROJOD ROXANA MAYRA*; KOTLER MÓNICA LIDIA; ALAIMO AGUSTINA

Ciudad Autónoma de Buenos Aires

Conferencia; Buenos Aires Research Conference on Autophagy 2017 "Molecular Mechanisms in Biology and Diseases"; 2017

Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires

Manganese (Mn) is an essential trace metal which plays a critical role in brain physiology. However, upon overexposure, Mn accumulates in brain, leading to the development of a Parkinsonism known as Manganism. Our lab is focused on the role of glial cells, namely microglia and astrocytes, in Mn neurotoxicity. Particularly, we are interested in the cellular pathways and signaling cascades that regulate cell death and survival. Autophagy is an intracellular degradation system, tightly connected with apoptosis by several molecular nodes of crosstalk. It is activated by different stressors, either having beneficial or harmful effects. Thus, we first inquired whether this mechanism is activated upon Mn exposure in glial cells. Then, we were interested in potential different roles for autophagy in astro- and microglial cell survival. For our studies, we employed astrocytoma and microglial cell lines (C6 and BV2, respectively). In both cell types, Mn induced autophagy activation, measured as an increase in LC3-II, Beclin 1 and p62. Interestingly, autophagy modulation employing 3-MA, rapamycin or mAtg5(K130R) resulted in different responses between both cell types. Moreover, Mn induced a ROS- dependent increase in acidic vesicles, accompanied by the occurrence of lysosomal membrane permeabilization (LMP). In this sense, both cathepsin B inhibitor (Ca-074 Me) or cathepsin D inhibitor (Pepstatin A) prevented Mn- induced cytotoxicity, being much more effective in astrocytoma cells. Overall, our studies demonstrate that autophagy in involved in Mn toxicity, differentially affecting cellular outcome in both astro- and microglial cells.