Reduced expression of peroxisome-proliferator activated receptor gamma coactivator-1α enhances α-synuclein oligomerization and down regulates AKT/GSK3β signaling pathway in human neuronal cells that inducibly express α-synuclein

• Published in: Neuroscience letters Vol. 473; no. 2; pp. 120 - 125
• Main Authors: Ebrahim, Abdul Shukkur, Ko, Li-wen, Yen, Shu-Hui
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.04.2010; Elsevier
• Subjects: Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; Human neuroblastoma cells; Medical sciences; Neurology; Parkinson's disease; PGC-1α; Vertebrates: nervous system and sense organs; α-Synuclein; α-Synuclein; PGC-1α; Parkinson's disease; Human neuroblastoma cells; Human; Nervous system diseases; Enzyme; Transferases; Parkinson disease; Cerebral disorder; Signal transduction; Cell line; Neuron; Glycogen synthase kinase-3β; Central nervous system disease; Degenerative disease; Peroxisome proliferator activated receptor; α-synuclein; Extrapyramidal syndrome
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2010.02.034

Intracellular accumulation of filamentous α-synuclein (α-Syn) aggregates to form Lewy bodies is a pathologic hallmark of Parkinson's disease. To determine whether mitochondrial impairment plays a role in the accumulation of α-Syn oligomer, we used 3D5 cell culture model of human neuronal type whereby conditional overexpression of wild-type α-Syn via the tetracycline-off (TetOff) induction mechanism results in formation of inclusions that exhibit many characteristics of Lewy bodies. In the present study, we compromised mitochondrial function in 3D5 cells by using shRNA to knockdown peroxisome-proliferator activated receptor gamma coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis and cellular energy metabolism and found that PGC-1α suppression at both protein and mRNA levels results in α-Syn accumulation (i.e. monomeric and oligomeric species in the TetOff-induced cells and monomeric only in the non-induced). These changes were accompanied with reduced mitochondrial potential as well as decreased levels of AKT, GSK3β (total and Ser 9-phosphorylated) and p53 that are important for cell survival. The extent to which these proteins decreased following PGC-1α knockdown, in contrast to what was demonstrable with the viability assay, is greater in the induced than the non-induced. Together these findings indicate that such knockdown increases the propensity to accumulate α-Syn oligomers, but the accumulation appears to have very little toxic impact to the neuronal cells.