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

Abstract

α-Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α-synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α-synuclein and regulate α-synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild-type α-synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of α-synuclein proteins promotes the decrease of LC3-II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant α-synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis.

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

“…It is intriguing that besides standard UPS and autophagy, mTOR activation is bound to the replacement of standard-with immune-proteasome subunits, providing a possible link between concomitant autophagy and UPS alterations, bridging altered proteostasis with neuroinflammation ( Figure 2) [74]. Autophagy constitutively operates in neurons as well as astrocytes and microglial cells, where it is key to degrading phagocytosed Aβ or α-syn while restraining pro-inflammatory cytokine release, apoptosis, and neurotoxicity [220][221][222]. Inflammatory stimuli which are known to induce the immunoproteasome may impair autophagy activity within either glial cells or neurons.…”

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

“…Studies in model systems with increased or abnormal α‐syn expression, or mutant LRRK2, have demonstrated compromised mitochondrial function such as decreased mitochondrial membrane potential and ATP production and increased oxidative stress (Butler et al., ; Erustes et al., 2017; Martin et al., ; Martinez et al., ; Melo, van Zomeren, Ferrari, Boddeke, & Copray, ; Mortiboys et al., ; Mortiboys, Johansen, Aasly, & Bandmann, ; Papkovskaia et al., ; Parihar, Parihar, Fujita, Hashimoto, & Ghafourifar, ; Sarafian et al., ; Su & Qi, ; Wang et al., ). While α‐syn null mice are protected against MPTP toxicity, and tg mice overexpressing human α‐syn may be more sensitive to MPTP‐induced toxicity (Dauer et al., ; Klivenyi et al., ; Song, Shults, Sisk, Rockenstein, & Masliah, ), LRRK2 knockout mice do not appear protected from MPTP (Andres‐Mateos et al., ).…”

Ghrelin mediated neuroprotection - A possible therapy for Parkinson's disease?

“…The association between autophagy and PD is further supported by several pre-clinical studies. For example, over-expression of αsynuclein, which is detrimental to rat cortical neurones (Wani et al, 2017), inhibits autophagy in an astrocyte cell line (Erustes et al, 2017). Mutant α-synuclein (A53T and A30P) impairs the efficacy of chaperone-mediated autophagy in rat neurones (Cuervo, 2004).…”

“…For example, deletion of the mTOR gene in a murine model of AD causes an increase in ATG3, ATG5, ATG7 and ATG12 (Caccamo, De Pinto, Messina, Branca, & Oddo, 2014). In cell and animal models of PD the over-expression of α-synuclein up-regulates mTOR and impairs autophagy (Erustes et al, 2017;Jiang et al, 2013;Wani et al, 2017).…”