The Nervous System Cytoskeleton under Oxidative Stress

Gardiner, John; Overall, Robyn L.; Marc, Jan

doi:10.3390/diseases1010036

Cited by 14 publications

(10 citation statements)

References 85 publications

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“…To the best of our knowledge, such an observation has not been reported before for LN. The cytoskeletal abnormalities recorded by CLEM tomography in two regions of a LN and two regions of another LN of a different brain donor using 2D CLEM support the idea that neurofilaments become disrupted, possibly through proximally experiencing an increase of oxidative stress 38,39 . The 3D STED data also showed that LN contain many mitochondria and lysosomes.…”

Section: Discussionmentioning

confidence: 57%

Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

Sharamoradian¹,

Britschgi

Stahlberg³

et al. 2017

Preprint

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SummaryParkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites, which are neuronal inclusions that are immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of this Lewy pathology is crucial to understanding pathogenesis and progression of the disease. Using correlative light and electron microscopy/tomography on brain tissue from five Parkinson’s disease brain donors, we identified α-synuclein immunopositive Lewy pathology and could show that the majority of these features including Lewy bodies and Lewy neurites primarily consists of a crowded membranous medley of vesicular structures and dysmorphic organelles. Only a small fraction of observed Lewy bodies contained predominant proteinaceous filaments, as previously described. The crowding of organellar components was confirmed by STED- based super-resolution microscopy, and high lipid content within the α-synuclein immunopositive inclusions was corroborated by confocal imaging, CARS/FTIR imaging and lipidomics. Applying this correlative high-resolution imaging and biophysical approach, we discovered in the postmortem brain of Parkinson’s patients a subcellular protein-lipid compartmentalization not previously described in Lewy pathology.

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Section: Discussionmentioning

confidence: 57%

Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

Sharamoradian¹,

Britschgi

Stahlberg³

et al. 2017

Preprint

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“…55 Oxidative stress is a key mechanism that causes aggregation of a number of proteins implicated in neurodegenerative disorders. 55,56 HQ induces F-actin aggregation through the phosphorylation of the P38/HSP27 cascade in ARPE-19 cells. 37 In the current study, we found that HQ also induced F-actin aggregation, P38 activation, and HSP27 phosphorylation in donor RPE cells, and RSG cotreatment abrogated these effects.…”

Section: Discussionmentioning

confidence: 99%

Risuteganib Protects against Hydroquinone–induced Injury in Human RPE Cells

Yang

Shao

Besley

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Cigarette smoking has been implicated in the pathogenesis of AMD. Integrin dysfunctions have been associated with AMD. Herein, we investigate the effect of risuteganib (RSG), an integrin regulator, on RPE cell injury induced by hydroquinone (HQ), an important oxidant in cigarette smoke. METHODS. Cultured human RPE cells were treated with HQ in the presence or absence of RSG. Cell death, mitochondrial respiration, reactive oxygen species production, and mitochondrial membrane potential were measured by flow cytometry, XFe24 analyzer, and fluorescence plate reader, respectively. Whole transcriptome analysis and gene expression were analyzed by Illumina RNA sequencing and quantitative PCR, respectively. F-actin aggregation was visualized with phalloidin. Levels of heme oxygenase-1, P38, and heat shock protein 27 proteins were measured by Western blot. RESULTS. HQ induced necrosis and apoptosis, decreased mitochondrial bioenergetics, increased reactive oxygen species levels, decreased mitochondrial membrane potential, increased F-actin aggregates, and induced phosphorylation of P38 and heat shock protein 27. HQ, but not RSG alone, induced substantial transcriptome changes that were regulated by RSG cotreatment. RSG cotreatment significantly protected against HQ-induced necrosis and apoptosis, prevented HQ-reduced mitochondrial bioenergetics, decreased HQ-induced reactive oxygen species production, improved HQ-disrupted mitochondrial membrane potential, reduced F-actin aggregates, decreased phosphorylation of P38 and heat shock protein 27, and further upregulated HQ-induced heme oxygenase-1 protein levels. CONCLUSIONS. RSG has no detectable adverse effects on healthy RPE cells, whereas RSG cotreatment protects against HQ-induced injury, mitochondrial dysfunction, and actin reorganization, suggesting a potential role for RSG therapy to treat retinal diseases such as AMD.

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“…In the event of oxidative stress, NFs are phosphorylated, leading to the formation of protein aggregates. In AD brains, for example, there is an increased N-malondialdehydelysine formation which destroys NFL proteins [44] . Therefore, cerebellar degeneration associated with NaN 3 and AlCl 3 -induced AD involves the dysregulation of NFL and possibly other cytoskeletal proteins in the cerebellum of rats, because cytoskeletal components are interconnected through cross-linking proteins, and damage to one component affects the entire cytoskeletal network.…”

Section: Gbc Prevents Astrogliosis and Nf Pathology In Cerebellar Cortexmentioning

confidence: 99%

Cerebellar Molecular and Cellular Characterization in Rat Models of Alzheimer's Disease: Neuroprotective Mechanisms of <b><i>Garcinia</i></b> Biflavonoid Complex

et al. 2017

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Background: Recent evidences suggest that cerebellar degeneration may be associated with the development of Alzheimer's disease (AD). However, previous reports were mainly observational, lacking substantial characterization of cellular and molecular cerebellar features during AD progression. Purpose: This study is aimed at characterizing the cerebellum in rat models of AD and assessing the corresponding neuroprotective mechanisms of Garcinia biflavonoid complex (GBc). Methods: Male Wistar rats were grouped and treated alone or in combination with PBS (ad libitum)/day, corn oil (CO; 2 mL/kgBw/day), GBc (200 mg/kgBw/day), sodium azide (NaN₃) (15 mg/kgBw/day) and aluminium chloride (AlCl₃) (100 mg/kgBw/day). Groups A and B received PBS and CO, respectively; C received GBc; D received NaN₃; E received AlCl₃; F received NaN₃ then GBc subsequently; G received AlCl₃ then GBc subsequently; H received NaN₃ and GBc simultaneously while I received AlCl₃ and GBc simultaneously. Following treatments, cerebellar cortices were processed for histology, immunohistochemistry and colorimetric assays. Results: Our data revealed that cryptic granule neurons and pyknotic Purkinje cell bodies (characterized by short dendritic/axonal processes) correspond to indistinctly demarcated cerebellar layers in rats treated with AlCl₃ and NaN₃. These correlates, with observed hypertrophic astrogliosis, increased the neurofilament deposition, depleted the antioxidant system-shown by expressed superoxide dismutase and glutathione peroxidase, and cerebellar glucose bioenergetics dysfunction-exhibited in assayed lactate dehydrogenase and glucose-6-phosphate dehydrogenase. We further showed that GBc reverses cerebellar degeneration through modulation of neurochemical signaling pathways and stressor molecules that underlie AD pathogenesis. Conclusion: Cellular, molecular and metabolic neurodegeneration within the cerebellum is associated with AlCl₃ and NaN₃-induced AD while GBc significantly inhibits corresponding neurotoxicity and is more efficacious when pre-administered.

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The Nervous System Cytoskeleton under Oxidative Stress

Cited by 14 publications

References 85 publications

Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

Risuteganib Protects against Hydroquinone–induced Injury in Human RPE Cells

Cerebellar Molecular and Cellular Characterization in Rat Models of Alzheimer's Disease: Neuroprotective Mechanisms of <b><i>Garcinia</i></b> Biflavonoid Complex

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