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

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Parkinson disease (PD) is a disease directly linked to age, affecting 0.5% to 1% of persons 65 to 69 years old, increasing to 1% to 3% in populations 80 years and older (Nussbaum & Ellis, 2003). The main feature of PD is the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. In addition, protein aggregates, known as Lewy bodies, are detected in the cytoplasm of these neurons. The main component of these protein aggregates is α‐synuclein (Spillantini et al., 1997). The physiological function of α‐synuclein remains poorly understood. It is believed to be associated with neurotransmitter trafficking, mitochondrial Ca2+ homeostasis, and mitochondrial morphology regulation (Calì, Ottolini, Negro, & Brini, 2012). α‐Synuclein is a small 14‐kDa protein encoded by the gene SNCA (Maroteaux, Campanelli, & Scheller, 1988). Mutations in SNCA lead to the synthesis of mutant proteins, such as A53T and A30P, both of which are associated with the familial forms of PD (Krüger et al., 1998; Polymeropoulos et al., 1997).
It has been proposed that neuronal cell death is directly linked to the accumulation of α‐synuclein, but the mechanism by which α‐synuclein accumulates in the cytoplasm is unclear. The failure of cellular degradation pathways, such as autophagy and the ubiquitin‐proteasome system, can turn the cells more prone to the formation of proteins aggregates, due to accumulation of α‐synuclein and other unfolded proteins. The role of autophagy in PD is still controversial, once its impairment is related to α‐synuclein aggregation and toxicity (Song et al., 2014), which still needs to be further investigated. The mechanism of toxicity mediated by α‐synuclein may involve the accumulation of this protein in the cytoplasm and its subsequent interaction with the mitochondrial membranes, thus inhibiting the activity of complex I of the mitochondrial electron transport chain, as observed in animal models and PD patient brains (Devi, Raghavendran, Prabhu, Avadhani, & Anandatheerthavarada, 2008; Schapira et al., 1990). Disruption of the mitochondrial electron transport chain can lead to the loss of mitochondrial membrane potential (ΔΨm) and the generation and accumulation of reactive oxygen species (Parihar, Parihar, Fujita, Hashimoto, & Ghafourifar, 2008). These events may activate apoptotic cell death pathways, in which the loss of ΔΨm is a central event. This leads to the release of apoptogenic molecules from the intermembrane space and the activation of caspases to induce cell death (Ong & Gustafsson, 2012).
Astrocytes play a key role in neuron physiology, including trophic support, gliotransmission, antioxidant activity, etc. (Bélanger & Magistretti, 2009; Wang & Bordey, 2008). These cells can mediate neuroprotection against oxidative stress and dopamine metabolic products in the SNpc (Bélanger & Magistretti, 2009; Chen et al., 2009; Episcopo et al., 2013). In response to inflammatory processes, reactive astrogliosis has been reported in animal models of PD (Wang, Liu, & Zhou, 2015). Lee et al. (2010) demonstrated the transfer of α‐synuclein from neuron to astrocytes by an endocytosis process, upregulating cytokines and activating inflammatory responses, which could be an important mediator in astroglial responses. In this way, the role of astrocytes in PD remains to be elucidated.
In this study, we investigated the effects of the overexpression of wild‐type (WT) α‐synuclein or the A30P and A53T mutant proteins on autophagy and apoptosis induction in immortalized astrocytes. Our results demonstrate that α‐synuclein overexpression in astrocytes sensitizes these cells to cytotoxic stimuli. This effect is predominantly related to α‐synuclein mutations, which may contribute to cell death and neurodegeneration.
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