Overexpression of α‐synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis

• Published in: Journal of neuroscience research Vol. 96; no. 1; pp. 160 - 171
• Main Authors: Erustes, Adolfo Garcia, Stefani, Fernanda Yakel, Terashima, Juliana Yoshie, Stilhano, Roberta Sessa, Monteforte, Priscila Totarelli, da Silva Pereira, Gustavo José, Han, Sang Won, Calgarotto, Andrana Karla, Hsu, Yi‐Te, Ureshino, Rodrigo Portes, Bincoletto, Cláudia, Smaili, Soraya Soubhi
• Format: Journal Article
• Language: English
• Published: United States 01.01.2018
• Subjects: A30P; A53T; alpha-Synuclein - biosynthesis; alpha-Synuclein - genetics; Animals; Apoptosis - physiology; Astrocytes - metabolism; Astrocytes - pathology; autophagy; Autophagy - physiology; Cell Line, Transformed; Cells, Cultured; Female; Gene Expression; Male; parkin; Parkinson disease; Rats; Rats, Wistar; α‐synuclein; Parkinson disease; autophagy; A53T; parkin; A30P; α-synuclein
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.24092

α‐Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α‐synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α‐synuclein and regulate α‐synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild‐type α‐synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of α‐synuclein proteins promotes the decrease of LC3‐II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant α‐synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis. Our data demonstrate that the overexpression of α‐synucleins (wild‐type and mutants A30P and A53T) in immortalized astrocyte cell lines potentiates depolarization of mitochondrial membrane potential, with an increase in parkin expression and a decrease of autophagic activity. The inhibition of autophagy may result in an increase of apoptosis.