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1

The interplay between parkin and alpha‑synuclein; possible implications for the pathogenesis of Parkinson’s disease

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Jesko H., Lenkiewicz A. M., Wilkaniec A., Adamczyk A.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr 3
Parkin and alpha‑synuclein (α‑syn) are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Oligomerization/ aggregation and excessive secretion of α‑syn contributes to PD through free radical stress, mitochondrial impairment, and synaptic dysfunction. Parkin, an E3 ubiquitin ligase, is considered to be a pleiotropic, neuroprotective protein that modulates metabolic turnover and the accumulation of α‑syn. This is in addition to parkin’s role in counteracting the more distant effects of α‑syn on cellular survival by altering proteasomal, autophagic, and calpain‑mediated protein degradation pathways that can reduce α‑syn levels. Moreover, parkin regulates mitochondrial turnover, cell survival, and immune phenomena – processes that are all known to be disturbed in PD. In addition, parkin might have an impact on the spreading and propagation of α‑syn by controlling its post‑translational modifications. On the other hand, recent research has shown that α‑syn oligomers affect the expression, post‑translational modification, and activity of parkin. This review focuses on the molecular mechanisms of cross‑talk between parkin and α‑syn in PD. The physical and functional interactions between α‑syn and parkin, which have been incompletely characterized to‑date, may present a new therapeutic avenue in PD and related synucleinopathies. The development of effective, clinically feasible modulators may offer great hopes for the therapy of PD.
2

The involvement of purinergic signaling in mitochondria dysfunction induced by Alpha-synuklein

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Lenkiewicz A. M., Wilkaniec A., Adamczyk A.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: The purinergic P2 receptors for adenosine 5’-triphosphate (ATP) have been shown to be involved in neurodegenerative disorders including Parkinson’s (PD) and Alzheimer’s diseases (AD). However, the mechanisms underlying the disturbances in ATP-mediated neurotransmission is not clear. Our previous studies support the idea that α-Synuclein (ASN) oligomerisation and its intercellular spreading play a pivotal role in progressive development of these neurodegenerative disorders. Therefore, the aim of our study is to examine the role of purinergic P2 receptors in extracellular ASN evoked mitochondria dysfunction and cell death. METHODS: The experiments were performed in human SH-SY5Y neuroblastoma cells differentiated with the all-trans retinoic acid (ATRA) using immunochemical, spectrophotometrical, radiochemical and spectrofluorometrical methods. RESULTS: Our study showed that exogenously added ASN (10 µM) induces release of ATP from SH-SY5Y cells leading to activation of P2 receptors and extracellular Ca2+ influx. Moreover, ASN treatment results in mitochondria dysfunction manifested by decrease of intracellular ATP level and dysregulation of mitochondria enzymes expression. All mentioned dysfunctions lead to SH-SY5Y cell death. It was demonstrated hat selective purinergic P2 receptors antagonist, PPADS (200 µM), significantly prevented ASN-evoked Ca2+ influx, decrease of intracellular ATP level and SH-SY5Y cell death. CONCLUSIONS: Summarizing, ASN may exerts its toxic effect via purinergic P2 receptors activation leading to impairment of calcium homeostasis, mitochondria dysfunction and cell death. We suggest that the P2 signaling pathway could be a therapeutic target for ASN toxicity in neurodegenerative disorders. Supported by NCN grants: 2013/09/D/NZ3/01359 to A.W. and 2012/05/B/NZ3/02047 to A.A.
3

P2X7 receptor mediates extracellular alpha-synuclein-induced mitochondrial dysfunction in neuroblastoma SH-SY5Y cells

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Wilkaniec A., Lenkiewicz A. M., Czapski G. A., Sulkowski G., Adamczyk A.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: α‑Synuclein (ASN) accumulation and mitochondrial dysfunction are central to the pathogenesis of most forms of Parkinson’s disease (PD) and appear to intersect, but how the two are related to each other has remained elusive. Recent research emphasised the important role of purinergic signalling dysfunction in PD. While the significant role of purinergic P2 family receptors in mitochondrial dysfunction is well known, the interaction of extracellular soluble ASN with purinergic receptors as well as the involvement of this interaction on mitochondria are not yet studied. AIM(S): The aim of this study was to investigate the effect of ASN on P2 purinergic signalling and the involvement of purinergic receptors in mitochondrial dysfunction. METHOD(S): As a research model we used neuroblastoma SH-SY5Y cell line as well as rat synaptoneurosomes treated with exogenous soluble ASN. The experiments were performed using spectrofluorometric, radiochemical and immunochemical methods. RESULTS: We found that exogenous ASN directly interacts with purinergic P2X7 receptor leading to its activation and intracellular free calcium mobilization in neuronal cells and nerve endings. Activation of P2X7 receptors leads to pannexin 1 recruitment and increased ATP release. Furthermore, ASN treatment induced mitochondrial dysfunction: changes in mitochondrial redox state, decrease in mitochondria membrane potential and elevation of mitochondrial superoxide production. This resulted in decreased synthesis of ATP and ultimately cell death. Importantly, treatment with non-selective (PPADS) or selective (AZ 11645373) P2X7 antagonist reversed the ASN-induced mitochondrial damage and prevented SH-SY5Y cells death. CONCLUSIONS: Our data indicated that P2X7 receptor activation is responsible for ASN-induced mitochondrial dysfunction. Thus, interference with P2X7 signalling seems to be a promising strategy for the prevention or therapy of PD and other neurodegenerative disorders. FINANCIAL SUPPORT: Supported by the NSC grant 2013/09/D/NZ3/0135.
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