Alpha-Synuclein Preformed Fibrils Induce Cellular Senescence in Parkinson’s Disease Models

Verma, Dinesh; Seo, Bo Am; Ghosh, Anurupa; Shi, Xun; Hernandez-Quijada, Karina; Andersen, Julie K.; Ko, Han Seok; Kim, Yong Hwan

doi:10.3390/cells10071694

Cited by 45 publications

(54 citation statements)

References 36 publications

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“…In another recent study described here, PFF gave rise to activated neuroglia, senescent neuroglia and neuronal death ( Verma et al, 2021 ). MPP + or PFF treatment of cultured dopaminergic rat N27 cells caused the cells to express senescence markers, such as reduced levels of Lamin B1 and HMGB1 and increased levels of p16 and p21.…”

Section: Interactions Between α-Synucleinopathy and Neuroglial Senesc...mentioning

confidence: 62%

“…Lamnin B1, HMGB1, and SATB1 were reduced, p21 levels were increased and p16 levels remained unchanged in postmortem PD brains compared to control midbrain tissues. The experimental results from Verma et al (2021) highlights how pathologic α-synuclein instigates simultaneous neuroglial senescence and neuroglial activation that eventually lead to PD-relevant neuronal death.…”

Section: Interactions Between α-Synucleinopathy and Neuroglial Senesc...mentioning

confidence: 99%

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Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

et al. 2022

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Parkinson’s disease (PD) is the most common movement disorder and the second most prevalent neurodegenerative disease after Alzheimer’s disease. Despite decades of research, there is still no cure for PD and the complicated intricacies of the pathology are still being worked out. Much of the research on PD has focused on neurons, since the disease is characterized by neurodegeneration. However, neuroglia has become recognized as key players in the health and disease of the central nervous system. This review provides a current perspective on the interactive roles that α-synuclein and neuroglial senescence have in PD. The self-amplifying and cyclical nature of oxidative stress, neuroinflammation, α-synucleinopathy, neuroglial senescence, neuroglial chronic activation and neurodegeneration will be discussed. Finally, the compelling role that senolytics could play as a therapeutic avenue for PD is explored and encouraged.

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Section: Interactions Between α-Synucleinopathy and Neuroglial Senesc...mentioning

confidence: 62%

Section: Interactions Between α-Synucleinopathy and Neuroglial Senesc...mentioning

confidence: 99%

Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

et al. 2022

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“…Alpha-synuclein, a pathological marker of Parkinson disease, is strongly expressed in the nuclei and synapses of neurons and is physiologically assumed to play an important role in synaptic transmission; however, its normal function remains unclear [ 10 , 11 , 95 , 96 ]. In the early stage of Parkinson disease, soluble alpha-synuclein fibrils are thought to exert neurotoxic effects, and they may act as a TLR4 ligand to induce neuroinflammation in microglia and astrocytes, leading to further neurological damage [ 10 , 11 , 95 , 96 , 112 , 113 ]. In animal models, inflammatory changes were observed in astrocytes and microglia in the substantia nigra after the injection of alpha-synuclein into the striatum and prior to pathological changes in the substantia nigra neurons, suggesting that the initial biological response to alpha-synuclein may be TLR4-mediated neuroinflammation [ 114 , 115 ].…”

Section: Dopamine Alpha-synuclein and Tlr4mentioning

confidence: 99%

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

Takahashi

Mashima

2022

Antioxidants

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Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.

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“…Studies with mice demonstrated the accumulation of senescent astrocytes and microglia following the injection of alpha-synuclein pre-formed fibrils into the brain. MPP + was also shown to stimulate cellular senescence [ 87 ]. Excitingly, paraquat-induced PD symptoms in mice were mitigated by killing senescent cells [ 88 ].…”

Section: Interventional Strategies To Correct Dysfunctional Mqc and D...mentioning

confidence: 99%

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Curtis

Seeds²,

Mattson

et al. 2022

Cells

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Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.

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Alpha-Synuclein Preformed Fibrils Induce Cellular Senescence in Parkinson’s Disease Models

Cited by 45 publications

References 36 publications

Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

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