Parkinson disease

European Journal of Neurology, Journal Year: 2019, Volume and Issue: 27(1), P. 27 - 42

Published: Oct. 21, 2019

Parkinson disease (PD) is the most common neurodegenerative movement disorder. In Europe, prevalence and incidence rates for PD are estimated at approximately 108–257/100 000 11–19/100 per year, respectively. Risk factors include age, male gender some environmental factors. The aetiology of in patients unknown, but different genetic causes have been identified. Although familial forms account only 5%–15% cases, studies on these families provided interesting insight genetics pathogenesis allowing identification genes implicated its offering critical insights into mechanisms disease. cardinal motor symptoms tremor, rigidity, bradykinesia/akinesia postural instability, clinical picture includes other non‐motor symptoms. Its diagnosis principally clinical, although specific investigations can help differential from parkinsonism. Pathologically, characterized by loss dopaminergic neurons pars compacta substantia nigra accumulation misfolded α‐synuclein, which found intra‐cytoplasmic inclusions called Lewy bodies. Currently available treatments offer good control do not modify evolution This article intended to provide a comprehensive, general practical review neurologist.

Language: Английский

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In vitro Models of Neurodegenerative Diseases

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: May 13, 2020

Neurodegenerative diseases are progressive degenerative conditions characterized by the functional deterioration and ultimate loss of neurons. These incurable debilitating affect millions people worldwide, therefore represent a major global health challenge with severe implications for individuals society. Recently, several neuroprotective drugs have failed in human clinical trials despite promising pre-clinical data, suggesting that conventional cell cultures animal models cannot precisely replicate pathophysiology. To bridge gap between studies, three-dimensional culture been developed from or cells, allowing effects new therapies to be predicted more accurately closely replicating some aspects brain environment, mimicking neuronal glial interactions, incorporating blood flow. In this review, we discuss relative merits different cerebral models, traditional latest high-throughput systems. We their advantages disadvantages as well potential investigate complex mechanisms neurodegenerative diseases. focus on vitro most frequent age-related disorders, such Parkinson's disease, Alzheimer's disease prion multiple sclerosis, chronic inflammatory affecting young adults.

Language: Английский

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The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease

Purinergic Signalling, Journal Year: 2020, Volume and Issue: 16(2), P. 167 - 174

Published: March 31, 2020

Language: Английский

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Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Feb. 18, 2020

Abstract Oxidative stress is a major pathogenic mechanism in Parkinson’s disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level decreased brains PD patients. Hence, clarifying molecular deficiency may help deepen our knowledge pathogenesis. Here we report that astrocytic dopamine D2 receptor (DRD2) regulates synthesis via PKM2-mediated Nrf2 transactivation. In addition find pyridoxine can dimerize PKM2 promote biosynthesis. Further experiments show supplementation increases resistance nigral dopaminergic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity wild-type mice as well Drd2 conditional knockout mice. We conclude dimerizing be potential target for treatment.

Language: Английский

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The role of genetics in Parkinson’s disease: a large cohort study in Chinese mainland population

Brain, Journal Year: 2020, Volume and Issue: 143(7), P. 2220 - 2234

Published: May 5, 2020

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset (sEOPD) in a mainland Chinese population clinical features mutation carriers. We performed multiplex ligation-dependent probe amplification assays whole-exome sequencing for 1676 unrelated patients with population, including 192 probands from families autosomal-recessive disease, 242 autosomal-dominant 1242 sEOPD (age at onset ≤ 50). According standards guidelines American College Medical Genetics Genomics, pathogenic/likely pathogenic variants 23 known disease-associated genes occurred more frequently cohort (65 192, 33.85%) than (10 242, 4.13%) (57 1242, 4.59%), which leads an overall molecular diagnostic yield 7.88% (132 1676). found that PRKN was most mutated gene (n = 83, 4.95%) present first evidence SNCA duplication LRRK2 p.N1437D variant China. In addition, several novel (p.V1447M p.Y1645S), ATP13A2 (p.R735X p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) TMEM230 (c.429delT/p.P144Qfs*2) were identified our cohort. Furthermore, age 132 genetic diagnoses (median, 31.5 years) about 14.5 years earlier without (i.e. non-carriers, median 46.0 years). Specifically, ATP13A2, PLA2G6, PRKN, or PINK1 significantly lower while carriers other similar non-carriers. The this populations. also detected 61 GBA possibly (3.64%) 59 p.L444P (3.52%). These results shed insight into manifestations China expand existing repertoire likely involved genes. Our data highlight importance testing < 40 years, especially those recessive inheritance pattern, who may benefit early diagnosis treatment.

Language: Английский

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The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Redox Biology, Journal Year: 2021, Volume and Issue: 47, P. 102134 - 102134

Published: Sept. 22, 2021

Parkinson's disease (PD) is a chronic neurodegenerative disorder that characterized by motor symptoms as result of loss dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied neuroinflammation, oxidative stress, formation α-synuclein aggregates. Celastrol, potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged neuroprotective agent. However, mechanisms which celastrol PD remain elusive. Here we show protects against dopamine neuron loss, mitigates relieves deficits MPTP-induced mouse model AAV-mediated human overexpression model. Whole-genome deep sequencing analysis revealed Nrf2, NLRP3 caspase-1 SNc may be associated with actions PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO Caspase-1-KO), identified inhibits inflammasome activation, nigrostriatal degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest axis serve key target treatment, highlight favorable properties for neuroprotection, making promising disease-modifying agent

Language: Английский

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Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 8, 2023

Nanomedicine-based anti-neuroinflammation strategy has become a promising dawn of Parkinson's disease (PD) treatment. However, there are significant gaps in our understanding the therapeutic mechanisms antioxidant nanomedicines concerning pathways traversing blood-brain barrier (BBB) and subsequent inflammation mitigation. Here, we report nanozyme-integrated metal-organic frameworks with excellent activity chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for treatment PD. These chiral nanozymes synthesized by embedding ultra-small platinum (Ptzymes) into L-chiral D-chiral imidazolate zeolite (Ptzyme@L-ZIF Ptzyme@D-ZIF). Compared to Ptzyme@L-ZIF, Ptzyme@D-ZIF shows higher accumulation brains male PD mouse models due longer plasma residence time more traverse BBB, including clathrin-mediated caveolae-mediated endocytosis. factors contribute superior efficacy reducing behavioral disorders pathological changes. Bioinformatics biochemical analyses suggest that inhibits neuroinflammation-induced apoptosis ferroptosis damaged neurons. The research uncovers biodistribution, metabolic variances, outcomes nanozymes-integrated ZIF platforms, providing possibilities devising anti-PD drugs.

Language: Английский

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Ultrasensitive spectrofluorimetric approach for quantitation of the novel antiparkinsonian drug safinamide in different matrices at nanogram levels: Assessment of greenness and whiteness profiles

Sustainable Chemistry and Pharmacy, Journal Year: 2024, Volume and Issue: 38, P. 101448 - 101448

Published: Jan. 19, 2024

Language: Английский

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Do your gut microbes affect your brain dopamine?

Psychopharmacology, Journal Year: 2019, Volume and Issue: 236(5), P. 1611 - 1622

Published: May 1, 2019

Language: Английский

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Role of the endolysosomal system in Parkinson’s disease

Journal of Neurochemistry, Journal Year: 2019, Volume and Issue: 150(5), P. 487 - 506

Published: July 9, 2019

Abstract Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–1.5% total population. While progress has been made in understanding mechanisms that lead to cell death late stages PD, for early, causal pathogenic events are still elusive. Recent developments PD genetics increasingly point at endolysosomal (E‐L) system dysfunction as early pathomechanism and key pathway affected PD. Clathrin‐mediated synaptic endocytosis, an integral part neuronal E‐L system, probably main target evident auxilin, RME‐8, synaptojanin‐1 mutations cause Autophagy, another important crucial maintaining proteostasis a healthy mitochondrial pool, especially neurons considering their inability divide requirement function entire life‐time. PINK1 Parkin severely perturb autophagy dysfunctional mitochondria (mitophagy), both body terminals dopaminergic neurons, leading Endolysosomal sorting trafficking also crucial, which complex multi‐compartmentalized neurons. VPS35 VPS13C noted these mechanisms. Mutations GBA comprise risk factor initiate pathology by compromising lysosomal function. This case ATP13A2 mutations. Interestingly, α‐synuclein LRRK2, proteins involved different steps components induce pathogenesis. In this review, we discuss genes linked how results image article Special Issue “Synuclein”.

Language: Английский

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