ORCID Profile
0000-0003-1640-0845
Current Organisations
Humboldt-Universität zu Berlin
,
University of Nottingham
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Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.FREERADBIOMED.2019.01.025
Abstract: Stress is a multimodal response involving the coordination of numerous body systems in order to maximize the chance of survival. However, long term activation of the stress response results in neuronal oxidative stress via reactive oxygen and nitrogen species generation, contributing to the development of depression. Stress-induced depression shares a high comorbidity with other neurological conditions including Alzheimer's disease (AD) and dementia, often appearing as one of the earliest observable symptoms in these diseases. Furthermore, stress and/or depression appear to exacerbate cognitive impairment in the context of AD associated with dysfunctional catecholaminergic signaling. Given there are a number of homologous pathways involved in the pathophysiology of depression and AD, this article will highlight the mechanisms by which stress-induced perturbations in oxidative stress, and particularly NO signaling, contribute to neurodegeneration.
Publisher: Frontiers Media SA
Date: 16-04-2019
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.FREERADBIOMED.2022.09.025
Abstract: Neurodegenerative diseases are associated with a multitude of dysfunctional cellular pathways. One major contributory factor is a redox stress challenge during the development of several protein misfolding conditions including Alzheimer's (AD), Parkinson's disease (PD), and less common conditions such as Creutzfeldt Jakob disease (CJD). CJD is caused by misfolding of the neuronal prion protein and is characterised by a neurotoxic unfolded protein response involving chronic endoplasmic reticulum stress, reduced protein translation and spongiosis leading subsequently to synaptic and neuronal loss. Here we have characterised prion disease in mice to assess redox stress components including nitrergic and oxidative markers associated with neuroinflammatory activation. Aberrant regulation of the homeostasis of several redox metals contributes to the overall cellular redox stress and we have identified altered levels of iron, copper, zinc, and manganese in the hippoc us of prion diseased mice. Our data show that early in disease, there is evidence for oxidative stress in conjunction with reduced antioxidant superoxide dismutase mRNA and protein expression. Moreover, expression of alent metal transporter proteins was reduced for Atp7b, Atox1, Slc11a2, Slc39a14 at 6-7 weeks but increased for Slc39a14 and Mt1 at 10 weeks of disease. Our data present evidence for a strong pro-oxidant environment and altered redox metal homeostasis in early disease pathology which both may be contributory factors to aggravating this protein misfolding disease.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-03-2021
Abstract: We present evidence that alleviating nitrergic stress during early phases of neurodegeneration reduces neuroinflammatory posttranslational nitric oxide signaling and glycation-assisted dysfunction in the hippoc us of prion-diseased mice, a mechanism which might be applicable to other protein-misfolding neurodegenerative conditions. We confirmed that pharmacological suppression of nitrergic activity reduces the formation of advanced glycation end-products, diminishes prion protein misfolding, and averts neuronal dysfunction. This intervention could present an approach to diminish the detrimental neuroinflammatory effects seen in neurodegeneration and highlights nitrergic stress and glycation signaling as putative targets for disease-modifying treatments. The correlation between protein glycation and prion misfolding—as reported for several other misfolding proteins—links NO signaling to the neuroprotective effects seen following NOS inhibition.
Publisher: Informa UK Limited
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 06-11-2018
DOI: 10.1101/463885
Abstract: Alterations in the neuromuscular system underlie several neuromuscular diseases and play critical roles in the development of sarcopenia, the age-related loss of muscle mass and function. Mammalian Myostatin (MST) and GDF11, members of the TGF-β superfamily of growth factors, are powerful regulators of muscle size in both model organisms and humans. Myoglianin (MYO), the Drosophila homolog of MST and GDF11, is a strong inhibitor of synaptic function and structure at the neuromuscular junction (NMJ), and a negative regulator of body weight and muscle size and function in flies. Here, we identified Plum, a cell surface immunoglobulin homologous to mammalian developmental regulators Protogenin and Nope, as a modulator of MYO function in the larval neuromuscular system. Reduction of Plum specifically in the larval body-wall muscles abolishes the previously demonstrated positive effect of attenuated MYO signalling on both muscle size and neuromuscular junction structure and function, likely by de-sequestrating the remaining MYO. In addition, downregulation of Plum on its own results in decreased synaptic strength and body weight, classifying Plum as a (novel) regulator of neuromuscular function and body (muscle) size. These findings offer new insights into possible regulatory mechanisms behind ageing- and disease-related neuromuscular dysfunctions in humans and identify potential targets for therapeutic interventions.
Publisher: Public Library of Science (PLoS)
Date: 27-04-2023
DOI: 10.1371/JOURNAL.PPAT.1011309
Abstract: Prion diseases, also known as transmissible spongiform encephalopathies, are rare, progressive, and fatal neurodegenerative disorders, which are caused by the accumulation of the misfolded cellular prion protein (PrP C ). The resulting cytotoxic prion species, referred to as the scrapie prion isoform (PrP Sc ), assemble in aggregates and interfere with neuronal pathways, ultimately rendering neurons dysfunctional. As the prion protein physiologically interacts with redox-active metals, an altered redox balance within the cell can impact these interactions, which may lead to and facilitate further misfolding and aggregation. The initiation of misfolding and the aggregation processes will, in turn, induce microglial activation and neuroinflammation, which leads to an imbalance in cellular redox homeostasis and enhanced redox stress. Potential approaches for therapeutics target redox signalling, and this review illustrates the pathways involved in the above processes.
Publisher: Public Library of Science (PLoS)
Date: 09-04-2018
Publisher: Springer Science and Business Media LLC
Date: 18-06-2018
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/9782346
Publisher: MDPI AG
Date: 28-08-2023
Abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD) therefore, the resulting disease is known as C9ALS/FTD. Here, we employ a Drosophila melanogaster model of C9ALS/FTD (C9 model) to investigate a role for specific medium-chain fatty acids (MCFAs) in reversing pathogenic outcomes. Drosophila larvae overexpressing the ALS-associated dipeptide repeats (DPRs) in the nervous system exhibit reduced motor function and neuromuscular junction (NMJ) defects. We show that two MCFAs, nonanoic acid (NA) and 4-methyloctanoic acid (4-MOA), can ameliorate impaired motor function in C9 larvae and improve NMJ degeneration, although their mechanisms of action are not identical. NA modified postsynaptic glutamate receptor density, whereas 4-MOA restored defects in the presynaptic vesicular release. We also demonstrate the effects of NA and 4-MOA on metabolism in C9 larvae and implicate various metabolic pathways as dysregulated in our ALS model. Our findings pave the way to identifying novel therapeutic targets and potential treatments for ALS.
Publisher: American Society for Clinical Investigation
Date: 19-12-2016
DOI: 10.1172/JCI87526
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Joern R Steinert.