Nutrient deprivation induces α-synuclein aggregation through endoplasmic reticulum stress response and SREBP2 pathway

• Published in: Frontiers in aging neuroscience Vol. 6; p. 268
• Main Authors: Jiang, Peizhou, Gan, Ming, Lin, Wen-Lang, Yen, Shu-Hui C
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 2014; Frontiers Media S.A
• Subjects: Aggregation; Apoptosis; Autophagy; Cell viability; Cellular stress response; Cholesterol; Endoplasmic reticulum; er stress; Genes; Immunoglobulins; Laboratory animals; Lewy bodies; Lovastatin; Movement disorders; Neurodegenerative diseases; Neuroscience; nutrient deprivation; Parkinson's disease; Phagocytosis; Phosphorylation; Polyglutamine; Protein folding; Synuclein; Trinucleotide repeat diseases; α-Synuclein; autophagy; nutrient deprivation; ER stress; SREBP2; aggregation; Parkinson’s disease; α-synuclein
• ISSN: 1663-4365; 1663-4365
• DOI: 10.3389/fnagi.2014.00268

Abnormal accumulation of filamentous α-synuclein (α-syn) in neurons, regarded as Lewy bodies (LBs), are a hallmark of Parkinson disease (PD). Although the exact mechanism(s) underlying LBs formation remains unknown, autophagy and ER stress response have emerged as two important pathways affecting α-syn aggregation. In present study we tested whether cells with the tetracycline-off inducible overexpression of α-syn and accumulating α-syn aggregates can benefit from autophagy activation elicited by nutrient deprivation (ND), since this approach was reported to effectively clear cellular polyglutamine aggregates. We found that nutrient deprivation of non-induced cells did not affect cell viability, but significantly activated autophagy reflected by increasing the level of autophagy marker LC3-II and autophagic flux and decrease of endogenous α-syn. Cells with induced α-syn expression alone displayed autophagy activation in an α-syn dose-dependent manner to reach a level comparable to that found in non-induced, nutrient deprived counterparts. Nutrient deprivation also activated autophagy further in α-syn induced cells, but the extent was decreased with increase of α-syn dose, indicating α-syn overexpression reduces the responsiveness of cells to nutrient deprivation. Moreover, the nutrient deprivation enhanced α-syn aggregations concomitant with significant increase of apoptosis as well as ER stress response, SREBP2 activation and cholesterolgenesis. Importantly, α-syn aggregate accumulation and other effects caused by nutrient deprivation were counteracted by knockdown of SREBP2, treatment with cholesterol lowering agent-lovastatin, or by GRP78 overexpression, which also caused decrease of SREBP2 activity. Similar results were obtained from studies of primary neurons with α-syn overexpression under nutrient deprivation. Together our findings suggested that down-regulation of SREBP2 activity might be a means to prevent α-syn aggregation in PD via reducing cholesterol levels.