A brief history of brain iron accumulation in Parkinson disease and related disorders

Journal of Neural Transmission, Год журнала: 2022, Номер 129(5-6), С. 505 - 520

Опубликована: Май 9, 2022

Abstract Iron has a long and storied history in Parkinson disease related disorders. This essential micronutrient is critical for normal brain function, but abnormal iron accumulation been associated with extrapyramidal century. Precisely why, how, when implicated neuronal death remains the subject of investigation. In this article, we review movement disorders, from first observations early twentieth century to recent efforts that view as novel therapeutic target diagnostic indicator.

Язык: Английский

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From the tyrosine hydroxylase hypothesis of Parkinson’s disease to modern strategies: a short historical overview

Journal of Neural Transmission, Год журнала: 2022, Номер 129(5-6), С. 487 - 495

Опубликована: Апрель 23, 2022

Abstract A time span of 60 years covers the detection catecholamines in brain, their function movement and correlation to Parkinson’s disease (PD). The clinical findings that orally given l -DOPA can alleviate or even prevent akinesia gave great hope for treatment PD. Attention focused on role tyrosine hydroxylase (TH) as rate-limiting enzyme formation catecholamines. It became evident driven is lowered Such results could only be obtained from studying human brain samples demonstrating necessity banks. Originally, a TH deficiency was suspected Studies were conducted properties: its induction turnover, complex regulation starting with cofactor requirements tetrahydrobiopterin ferrous iron, phosphorylation activity well inhibition by toxins regulatory feedback In course time, it neurodegeneration cell death dopaminergic neurons actual pathological process decrease cophenomenon. Nevertheless, immunochemistry has ever since been valuable tool study neuronal pathways, various animal models neurotoxicity cultures, which have used test potential neuroprotective strategies.

Язык: Английский

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Ferroptosis and Neurodegenerative Diseases: Insights into the Regulatory Roles of SLC7A11

Cellular and Molecular Neurobiology, Год журнала: 2023, Номер 43(6), С. 2627 - 2642

Опубликована: Март 29, 2023

Язык: Английский

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Parkinson’s Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(4), С. 2009 - 2009

Опубликована: Фев. 7, 2024

The core pathological event in Parkinson’s disease (PD) is the specific dying of dopamine (DA) neurons substantia nigra pars compacta (SNc). reasons why SNc DA are especially vulnerable and idiopathic PD has only been found humans still puzzling. two main underlying factors neuron vulnerability appear related to high production, namely (i) toxic effects cytoplasmic metabolism (ii) continuous cytosolic Ca2+ oscillations absence Ca2+-buffer protein calbindin. Both cause oxidative stress by producing highly reactive quinones increasing intra-mitochondrial concentrations, respectively. High expression human cell bodies suggested abundant presence DA-derived pigment neuromelanin, which not such abundance other species associated with toxicity at higher levels. created their production system, despite fact that SN does use unusually amounts energy, explains sensitive various genetic environmental create mitochondrial damage thereby promote PD. Aging increases multiple risk for PD, and, a large extent, accelerated aging. To prevent neurodegeneration, possible approaches discussed here (1) reducing accumulation, (2) blocking oscillations, (3) providing bioenergetic support.

Язык: Английский

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Virus-induced brain pathology and the neuroinflammation-inflammation continuum: the neurochemists view

Journal of Neural Transmission, Год журнала: 2024, Номер unknown

Опубликована: Янв. 23, 2024

Abstract Fascinatingly, an abundance of recent studies has subscribed to the importance cytotoxic immune mechanisms that appear increase risk/trigger for many progressive neurodegenerative disorders, including Parkinson’s disease (PD), Alzheimer’s (AD), amyotrophic lateral sclerosis, and multiple sclerosis. Events associated with neuroinflammatory cascades, such as ageing, immunologic dysfunction, eventually disruption blood–brain barrier “cytokine storm”, be orchestrated mainly through activation microglial cells communication neurons. The inflammatory processes prompt cellular protein dyshomeostasis. share a common feature marked by characteristic pathological hallmarks abnormal neuronal accumulation. These Lewy bodies contain misfolded α-synuclein aggregates in PD or case AD, they are Aβ deposits tau-containing neurofibrillary tangles. Subsequently, these further elicit neurotoxic events which contribute onset neurodegeneration its progression aggravation neuroinflammation. However, there is caveat exclusively linking neuroinflammation neurodegeneration, since it’s highly unlikely dysregulation only factor contributes manifestation disorders. It unquestionably complex interaction other factors genetics, age, environment. This endorses “multiple hit hypothesis”. Consequently, if host genetic susceptibility coupled age-related weakened system, this makes them more susceptible virus/bacteria-related infection. may trigger chronic leading dyshomeostasis accumulation, finally, lead destruction. Here, we differentiate “neuroinflammation” “inflammation” regard involvement barrier, seems intact but defect inflammation. There neuroinflammation-inflammation continuum virus-induced brain affection. Therefore, propose staging process, might developed adding blood- CSF parameters, their stage-dependent composition severeness grade. If so, suitable optimise therapeutic strategies fight beginning avoid inflammation at all.

Язык: Английский

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Toxic interactions between dopamine, α-synuclein, monoamine oxidase, and genes in mitochondria of Parkinson’s disease

Journal of Neural Transmission, Год журнала: 2024, Номер 131(6), С. 639 - 661

Опубликована: Янв. 9, 2024

Язык: Английский

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The Molecular Mechanisms of Ferroptosis and Its Role in Blood-Brain Barrier Dysfunction

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Май 19, 2022

The blood-brain barrier (BBB) is a selective, semi-permeable layer of endothelial cells that protects the central nervous system from harmful substances circulating in blood. It one important barriers system. BBB dysfunction an early pathophysiological change observed diseases. There are few treatments for dysfunction, so this motivates review. Ferroptosis novel cell death mode caused by iron-mediated lipid peroxidation accumulation, which has recently attracted more attention due to its possible role disorders. Studies have shown and iron accumulation related especially expression tight junction proteins. Therefore, examination relationship between ferroptosis may reveal new targets treatment brain

Язык: Английский

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Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives

Antioxidants, Год журнала: 2023, Номер 12(3), С. 575 - 575

Опубликована: Фев. 24, 2023

Several studies have reported that the tetracycline (TC) class antibiotic doxycycline (DOX) is effective against Parkinson's disease (PD) pathomechanisms. The aim of present work was three-fold: (i) Establish a model system to better characterize neuroprotection by DOX; (ii) Compare rescue effect DOX other TC antibiotics; (iii) Discover novel neuroprotective TCs having reduced activity. For that, we used cultures mouse midbrain dopamine (DA) neurons and experimental conditions iron-mediated oxidative damage, key mechanism in PD pathobiology. We found antibiotic, demeclocycline (DMC), provided sustained protection DA enduring insults, whereas chlortetracycline non-TC antibiotics did not. Most interestingly, non-antibiotic derivatives DMC, i.e., DDOX DDMC, respectively, were also robustly protective for neurons. Interestingly, DOX, DDOX, DDMC remained until advanced stages neurodegeneration, effects observable regardless degree maturity cultures. Live imaging with fluorogenic probes DHR-123 TMRM revealed operated preventing intracellular stress mitochondrial membrane depolarization, cellular perturbations occurring this as ultimate consequence ferroptosis-mediated lipid peroxidation. If oxidative/mitochondrial insults generated acutely, no longer neuroprotective, suggesting these compounds are mostly when neuronal damage chronic low-intensity. Overall, our data suggest derivatives, particularly those lacking activity, might be potential therapeutic utility combat low-level develop chronically course neurodegeneration.

Язык: Английский

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Oxidation of dopamine and related catechols in dopaminergic brain regions in Parkinson’s disease and during ageing in non-Parkinsonian subjects

Journal of Neural Transmission, Год журнала: 2024, Номер 131(3), С. 213 - 228

Опубликована: Янв. 18, 2024

Язык: Английский

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Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review)

Experimental and Therapeutic Medicine, Год журнала: 2023, Номер 27(1)

Опубликована: Ноя. 21, 2023

Parkinson's disease (PD) is a common neurodegenerative pathology whose major clinical symptoms are movement disorders. The main pathological characteristics of PD the selective death dopaminergic (DA) neurons in pars compacta substantia nigra and presence Lewy bodies containing α-synuclein (α-Syn) within these neurons. associated with numerous risk factors, including environmental genetic mutations aging. In many cases, complex interplay factors leads to onset PD. mutated α-Syn gene, which expresses pathologicalα-Syn protein, can cause Another important feature neuroinflammation, conducive neuronal death. able interact certain cell types brain, through phagocytosis degradation by glial cells, activation inflammatory pathways transmission between cells neurons, interactions peripheral immune α-Syn. addition aforementioned may also be aging, as prevalence increases advancing age. aging process impairs cellular clearance mechanism, chronic inflammation accumulation intracellular α-Syn, results DA present review, age-associated pathogenicity brain discussed facilitate understanding mechanisms pathogenesis, potentially provide insight for future treatment

Язык: Английский

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