title: Nutrient deprivation induces α-synuclein aggregation through endoplasmic reticulum stress response and SREBP2 pathway.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine Jacksonville, FL, USA.
authors.forename: Peizhou
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine Jacksonville, FL, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Gan
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine Jacksonville, FL, USA.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine Jacksonville, FL, USA.
authors.forename: Shu-Hui C
authors.initials: SH
authors.lastname: Yen
keywords: ER stress; Parkinson’s disease; SREBP2; aggregation; autophagy; nutrient deprivation; α-synuclein