The role of alpha-synuclein as ferrireductase in neurodegeneration associated with Parkinson’s disease

Sian-Hülsmann, Jeswinder; Riederer, Peter

doi:10.1007/s00702-020-02192-0

Cited by 24 publications

(25 citation statements)

References 52 publications

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“…Furthermore, oligomeric structures produced from α-synuclein inclusions have been shown to be structurally related to amyloid beta peptide fibrils found in Alzheimer's disease [56]. This may indicate some common iron-mediated neurodegenerative pathway [57][58][59]. In addition, an oxidative environment supports the aggregation of α-synuclein, thereby exacerbating the neurodegenerative pathology load [60,61].…”

Section: Disturbed Metabolic and Physiological Mechanismsmentioning

confidence: 99%

“…However, at high concentrations, IRP is bound by iron, which causes mRNA to undergo translation [99]. Indeed, the concentration of iron has been shown by using different analytical methodologies to be significantly increased in the SN of PD [48,59]. Some of the factors responsible for changes of α-synuclein may include a neurotoxin, amphipathic molecules (such as pesticides, herbicides), the presence of metal ions, a reduction in pH, and an increase in α-synuclein concentration.…”

Section: Genetic and α-Synuclein-related Pathological Processes In Pdmentioning

confidence: 99%

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The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Sian-Hülsmann

Riederer

2021

Cells

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The risk of Parkinson’s disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson’s disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

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Section: Disturbed Metabolic and Physiological Mechanismsmentioning

confidence: 99%

Section: Genetic and α-Synuclein-related Pathological Processes In Pdmentioning

confidence: 99%

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Sian-Hülsmann

Riederer

2021

Cells

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“…This process plays an eminent role in the pathophysiology of chronic neurodegeneration in PD. [21][22][23] In summary, these possible metabolic consequences of too high l-dopa dosing, respectively dopamine overflow, may accelerate progression of PD, the general ageing process and facilitate onset of dementia and neuropathy. 9 All these drawbacks of l-dopa therapy caused research on treatment alternatives for dopamine substitution.…”

Section: Dovepressmentioning

confidence: 99%

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

Müller¹

2021

JEP

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Parkinson's disease (PD) is the second most chronic neurodegenerative disorder worldwide. Deficit of monoamines, particularly dopamine, causes an individually varying compilation of motor and non-motor features. Constraint of presynaptic uptake extends monoamine stay in the synaptic cleft. This review discusses possible benefits of dopamine reuptake inhibition for the treatment of PD. Translation of this pharmacologic principle into positive clinical study results failed to date. Past clinical trial designs did not consider a mandatory, concomitant stable inhibition of glial monoamine turnover, i.e. with monoamine oxidase B inhibitors. These studies focused on improvement of motor behavior and levodopa associated motor complications, which are fluctuations of motor and non-motor behavior. Future clinical investigations in early, levodopa-and dopamine agonist naïve patients shall also aim on alleviation of non-motor symptoms, like fatigue, apathy or cognitive slowing. Oral levodopa/dopa decarboxylase inhibitor application is inevitably necessary with advance of PD. Monoamine reuptake (MRT) inhibition improves the efficacy of levodopa, the blood brain barrier crossing metabolic precursor of dopamine. The pulsatile brain delivery pattern of orally administered levodopa containing formulations results in synaptic dopamine variability. Ups and downs of dopamine counteract the physiologic principle of continuous neurotransmission, particularly in nigrostriatal, respectively mesocorticolimbic pathways, both of which regulate motor respectively non-motor behavior. Thus synaptic dopamine pulsatility overwhelms the existing buffering capacity. Onset of motor and non-motor complications occurs. Future MRT inhibitor studies shall focus on a stabilizing and preventive effect on levodopa related fluctuations of motor and non-motor behavior. Their long-term study designs in advanced levodopa treated patients shall allow a cautious adaptation of oral l-dopa therapy combined with a mandatory inhibition of glial monoamine turnover. Then the evidence for a preventive and beneficial, symptomatic effect of MRT inhibition on motor and non-motor complications will become more likely.

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“…The loss of ferrireductase activity in the cell would result in dyshomeostasis of iron (Fe 3+ /Fe 2+ ) and accumulation of the ROSassociated Fe 2+ . In this sense toxicity would be secondary to the loss of α-syn function, with ROS-modification of cellular components and subsequent initiation of cell death pathways attributed to excess Fe 2+ (McDowall et al, 2017;Sian and Peter, 2020). In a gain-of-function mechanism, α-syn can gain a toxic conformation capable of interacting with various cellular components resulting in cellular dysfunction (Sian and Peter, 2020).…”

Section: Cellular Toxicity Associated With α-Synucleinmentioning

confidence: 99%

“…In this sense toxicity would be secondary to the loss of α-syn function, with ROS-modification of cellular components and subsequent initiation of cell death pathways attributed to excess Fe 2+ (McDowall et al, 2017;Sian and Peter, 2020). In a gain-of-function mechanism, α-syn can gain a toxic conformation capable of interacting with various cellular components resulting in cellular dysfunction (Sian and Peter, 2020). Several in vitro and in vivo studies have implicated α-syn aggregation, principally the generation of prefibrillar oligomeric species, as the toxic species responsible for neurodegeneration in PD (Kahle et al, 2000;Danzer et al, 2007;Outeiro et al, 2008;Karpinar et al, 2009;Choi et al, 2013Choi et al, , 2015.…”

Section: Cellular Toxicity Associated With α-Synucleinmentioning

confidence: 99%

Recapitulating Parkinson’s disease pathology in a three-dimensional neural cell culture model

Taylor-Whiteley¹

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease (AD), occurring at a rate of 0.1%-0.2% of the population. The incidence of PD increases with advancing age, affecting 1% of the population over the age of 65. Extensive loss of dopaminergic neurons and aggregation of the protein α-synuclein (α-syn) into ubiquitin-positive Lewy bodies (LBs) represents a major neuropathological hallmark of PD. The impact of LB pathology on the disease pathogenesis is still largely unknown, with evidence suggesting small soluble oligomeric assemblies that precede LB development are the causative agent in PD. At present, the generation of large nuclear-associated LBs from endogenous wildtype α-syn, translationally regulated under its own promoter in human cell culture models, requires costly and time-consuming protocols. The primary objective of this thesis was to develop a more physiologically relevant cell culture model of PD that recapitulates the development of LB inclusions. Using a cell culture model of fully differentiated human SH-SY5Y neuroblastoma cells grown in three-dimensions (3D), cells were shown to develop LB-like pathology upon exposure to exogenous α-syn species. In contrast to most cell- and rodent based PD models, which exhibit multiple diffuse α-syn aggregates throughout the cytoplasm, a single large nuclear inclusion that is immunopositive for α-syn and ubiquitin is rapidly obtained in our model. However, phosphorylation of α-syn within these inclusions was not observed. This was achieved without the need for overexpression of α-syn or genetic modification of the cell line. To further explore the mechanism of LB formation the recently discovered programmed cell death pathway ferroptosis was investigated. Ferroptosis is an irondependent cell death pathway that shares similar pathogenic features with PD including elevated iron concentration, GSH depletion, lipid peroxidation and increased ROS. However, there are currently no studies that have explored whether α-syn is involved in ferroptotic cell death. Viability assays within the 3D cell culture model following treatment with ferroptosis and apoptosis inducers and qPCR of ferroptotic targets demonstrated resistance to this mechanism of programmed cell death. Nevertheless, treatment with iron was associated with some features of ferroptosis including increased ROS, some lipid peroxidation and reduced levels of glutathione peroxidase 4 (GPX4). Phosphorylation of α-syn at serine 129 (S129) was increased upon iron treatment and reduced following treatment with a ferroptosis inhibitor, liproxstatin-1. These results demonstrate the potential implications of iron exposure, α-syn aggregation, and ferroptosis in the pathogenesis of PD. The system described in this thesis provides an ideal tool to screen compounds to intervene therapeutically in LB formation, and to investigate the mechanisms involved in disease progression in synucleinopathies.

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The role of alpha-synuclein as ferrireductase in neurodegeneration associated with Parkinson’s disease

Cited by 24 publications

References 52 publications

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

Recapitulating Parkinson’s disease pathology in a three-dimensional neural cell culture model

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