Dataset Information

Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness.

ABSTRACT: Proteasomes are the central proteolytic machines that are critical for breaking down most of the damaged and abnormal proteins in human cells. Although universally applicable drugs are not yet available, the stimulation of proteasomal activity is being analyzed as a proof-of-principle strategy to increase cellular resistance to a broad range of proteotoxic stressors. These approaches have included the stimulation of proteasomes through the overexpression of individual proteasome subunits, phosphorylation, or conformational changes induced by small molecules or peptides. In contrast to these approaches, we evaluated a transcription-driven increase in the total proteasome pool to enhance the proteolytic capacity of degenerating retinal neurons. We show that overexpression of nuclear factor erythroid-2-like 1 (Nfe2l1) transcription factor stimulated proteasome biogenesis and activity, improved the clearance of the ubiquitin-proteasomal reporter, and delayed photoreceptor neuron loss in a preclinical mouse model of human blindness caused by misfolded proteins. The findings highlight Nfe2l1 as an emerging therapeutic target to treat neurodegenerative diseases linked to protein misfolding.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10348684 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness.

Wang Yixiao Y Snell Aaron A Dyka Frank M FM Colvin Elizabeth R ER Ildefonso Cristhian C Ash John D JD Lobanova Ekaterina S ES

Science advances 20230714 28

Proteasomes are the central proteolytic machines that are critical for breaking down most of the damaged and abnormal proteins in human cells. Although universally applicable drugs are not yet available, the stimulation of proteasomal activity is being analyzed as a proof-of-principle strategy to increase cellular resistance to a broad range of proteotoxic stressors. These approaches have included the stimulation of proteasomes through the overexpression of individual proteasome subunits, phosph ...[more]

PMID: 37450596

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Project description:There have been relatively few attempts to represent vision or blindness ontologically. This is unsurprising as the related phenomena of sight and blindness are difficult to represent ontologically for a variety of reasons. Blindness has escaped ontological capture at least in part because: blindness or the employment of the term 'blindness' seems to vary from context to context, blindness can present in a myriad of types and degrees, and there is no precedent for representing complex phenomena such as blindness.We explore current attempts to represent vision or blindness, and show how these attempts fail at representing subtypes of blindness (viz., color blindness, flash blindness, and inattentional blindness). We examine the results found through a review of current attempts and identify where they have failed.By analyzing our test cases of different types of blindness along with the strengths and weaknesses of previous attempts, we have identified the general features of blindness and vision. We propose an ontological solution to represent vision and blindness, which capitalizes on resources afforded to one who utilizes the Basic Formal Ontology as an upper-level ontology.The solution we propose here involves specifying the trigger conditions of a disposition as well as the processes that realize that disposition. Once these are specified we can characterize vision as a function that is realized by certain (in this case) biological processes under a range of triggering conditions. When the range of conditions under which the processes can be realized are reduced beyond a certain threshold, we are able to say that blindness is present. We characterize vision as a function that is realized as a seeing process and blindness as a reduction in the conditions under which the sight function is realized. This solution is desirable because it leverages current features of a major upper-level ontology, accurately captures the phenomenon of blindness, and can be implemented in many domain-specific ontologies.

Project description:ObjectiveTo estimate the economic impact for the society, generated as a consequence of the onset of loss of vision and irreversible legal blindness, for the main ophthalmologic diseases in Spain: glaucoma, diabetic retinopathy (DR), diabetic macular edema (DME), age-related macular degeneration (AMD) and high myopia (HM).MethodsA cost analysis model was developed to estimate the economic burden of glaucoma, DR, DME, AMD and HM over a 10-year time horizon (2021-2030), from a societal perspective in Spain. The epidemiological and economic parameters used in the model were obtained through a literature review. Prevalence, incidence, and progression stages were used to establish the epidemiological flows. Annual costs per patient from publications were included and classified into direct healthcare, direct non-healthcare and indirect costs. Costs from other countries were converted based on purchasing-power-parity (€EUR, PPP). Epidemiological parameters about population and cost results were validated by a panel of experts. All costs were adjusted to euros, 2021 (€, 2021), and using the Consumer Price Index (CPI) of the last 10 years, extrapolated to 2030 euros (€, 2030).ResultsIt was estimated that the total population of patients with the main diseases pathologies (glaucoma, DR, DME, AMD and HM) will increase to 7.99 million patients by 2030, representing an increase of 103%. The total cost by 2030 of all pathologies would amount to 99.8 billion euros. Direct non-healthcare costs account for the largest item (44%), followed by loss of productivity costs (38%), and direct healthcare costs (18%). The pathologies with the highest cumulative costs will be glaucoma (€33.6 billion) and DME (€19.8 billion).The greatest increment costs compared to 2021 will likely be generated by pathologies related to diabetes mellitus, such as DR (703%) and DME (317%).ConclusionsKnowing the costs associated with the pathologies that generate loss of vision and irreversible legal blindness is essential to understand the socioeconomic impact associated with these pathologies. Furthermore, the high cost of treating these diseases makes necessary to coordinate efforts between administrations, together with the support of patient associations, to meet their needs.

Project description:BackgroundIn the absence of accessible, good quality eye health services and inclusive environments, vision loss can impact individuals, households and communities in many ways, including through increased poverty, reduced quality of life and reduced employment. We aimed to estimate the annual potential productivity losses associated with reduced employment due to blindness and moderate and severe vision impairment (MSVI) at a regional and global level.MethodsWe constructed a model using the most recent economic, demographic (2018) and prevalence (2020) data. Calculations were limited to the working age population (15-64 years) and presented in 2018 US Dollars purchasing power parity (ppp). Two separate models, using Gross Domestic Product (GDP) and Gross National Income (GNI), were calculated to maximise comparability with previous estimates.FindingsWe found that 160.7 million people with MSVI or blindness were within the working age and estimated that the overall relative reduction in employment by people with vision loss was 30.2%. Globally, using GDP we estimated that the annual cost of potential productivity losses of MSVI and blindness was $410.7 billion ppp (range $322.1 - $518.7 billion), or 0.3% of GDP. Using GNI, overall productivity losses were estimated at $408.5 billion ppp (range $320.4 - $515.9 billion), 0.5% lower than estimates using GDP.InterpretationThese findings support the view that blindness and MSVI are associated with a large economic impact worldwide. Reducing and preventing vision loss and developing and implementing strategies to help visually impaired people to find and keep employment may result in significant productivity gains.FundingMJB is supported by the Wellcome Trust (207472/Z/17/Z). JR's appointment at the University of Auckland is funded by the Buchanan Charitable Foundation, New Zealand. The Lancet Global Health Commission on Global Eye Health was supported by grants from The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity (GR001061), NIHR Moorfields Biomedical Research Centre, The Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The SEVA Foundation, The British Council for the Prevention of Blindness and Christian Blind Mission. The funders had no role in the design, conduct, data analysis of the study, or writing of the manuscript.

Dataset Information

Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness.

Publications

Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness.

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