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

Peizhou Jiang,Shu-Hui C Yen,Wen-Lang Lin,Ming Gan

doi:10.3389/fnagi.2014.00268

Peizhou Jiang, Shu-Hui C Yen + Show 2 more

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https://doi.org/10.3389/fnagi.2014.00268

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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.

Highlights

Parkinson disease (PD) is a neurodegenerative disorder characterized pathologically by loss of dopaminergic neurons in the substantia nigra and abnormal accumulation of α-synuclein (α-syn) as filamentous aggregates in neuronal perikarya and processes referred to as Lewy bodies (LBs) and Lewy neurites (LNs), respectively (Cookson, 2005; Lippa et al, 2007)
MACROAUTOPHAGY IS PREDOMINANTLY RESPONSIBLE FOR α-SYN DEGRADATION IN 3D5 CELLS UPON NUTRIENT DEPRIVATION Previous studies have shown that wild type α-syn can be degraded by different pathways including proteasome, chaperone-mediated autophagy (CMA) and macroautophagy in neuronal cells (Webb et al, 2003; Vogiatzi et al, 2008)
It is worth noting that the cells we used here are only with endogenous α-syn because those with overexpressed α-syn are vulnerable to inhibitors under nutrient deprivation

Summary

Introduction

Parkinson disease (PD) is a neurodegenerative disorder characterized pathologically by loss of dopaminergic neurons in the substantia nigra and abnormal accumulation of α-synuclein (α-syn) as filamentous aggregates in neuronal perikarya and processes referred to as Lewy bodies (LBs) and Lewy neurites (LNs), respectively (Cookson, 2005; Lippa et al, 2007). The exact mechanisms underlying the formation of LBs and LNs remain unclear, a lot of attention has been drawn to identify etiological factors/pathways affecting α-syn aggregation either directly or indirectly. In this regard autophagy and unfolded protein response (UPR) have emerged as two pathways of importance (Hoozemans et al, 2007; Pan et al, 2008; Lynch-Day et al, 2012; Mercado et al, 2013). Exposure to ER stress inducers increased further the levels of α-syn assemblies (Jiang et al, 2010)

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