{"id":1718,"date":"2024-06-25T02:26:49","date_gmt":"2024-06-25T02:26:49","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/medphc\/?p=1718"},"modified":"2024-12-17T08:41:31","modified_gmt":"2024-12-17T08:41:31","slug":"insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system","status":"publish","type":"post","link":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/","title":{"rendered":"Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system"},"content":{"rendered":"\r\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone  wp-image-2565\" src=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/06\/20240625-KLR-300x169.jpg\" alt=\"\" width=\"950\" height=\"535\" srcset=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/06\/20240625-KLR-300x169.jpg 300w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/06\/20240625-KLR-1024x576.jpg 1024w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/06\/20240625-KLR-768x432.jpg 768w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/06\/20240625-KLR.jpg 1280w\" sizes=\"auto, (max-width: 950px) 100vw, 950px\" \/><\/p>\r\n<p><span style=\"font-size: 18pt;\"><strong>Summary<\/strong><\/span><\/p>\r\n<p><span style=\"font-size: 14pt;\">Xeroderma pigmentosum(XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stemcellsderivedfromXPpatients andhealthy relatives, performingfunctional multi-omicsonsamples duringneuronaldifferentiation.We showsubstantially increasedlevels of 50,8-cyclopurineand8-oxopurine in XPneuronalDNAsecondary tomarked oxidative stress. Furthermore,we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associatedwith phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.<\/span><\/p>\r\n<p>Full article: <a href=\"https:\/\/www.cell.com\/cell-reports\/fulltext\/S2211-1247(24)00571-0\">https:\/\/www.cell.com\/cell-reports\/fulltext\/S2211-1247(24)00571-0<\/a><\/p>\r\n","protected":false},"excerpt":{"rendered":"<p>Summary Xeroderma pigmentosum(XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using [&hellip;]<\/p>\n","protected":false},"author":9345,"featured_media":2565,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"default","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"default","adv-header-id-meta":"","stick-header-meta":"default","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"set","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[5],"tags":[],"class_list":["post-1718","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.4 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system - Pharmacology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system - Pharmacology\" \/>\n<meta property=\"og:description\" content=\"Summary Xeroderma pigmentosum(XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/\" \/>\n<meta property=\"og:site_name\" content=\"Pharmacology\" \/>\n<meta property=\"article:published_time\" content=\"2024-06-25T02:26:49+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-12-17T08:41:31+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/06\/20240625-KLR.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1280\" \/>\n\t<meta property=\"og:image:height\" content=\"720\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Woon Fei\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Woon Fei\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/\"},\"author\":{\"name\":\"Woon Fei\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#\/schema\/person\/ea3ccd10ab2f2bba51fd804396287cb0\"},\"headline\":\"Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system\",\"datePublished\":\"2024-06-25T02:26:49+00:00\",\"dateModified\":\"2024-12-17T08:41:31+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/\"},\"wordCount\":160,\"publisher\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#organization\"},\"image\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/06\/20240625-KLR.jpg\",\"articleSection\":[\"Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/\",\"url\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/insights-from-multi-omic-modeling-of-neurodegeneration-in-xeroderma-pigmentosum-using-an-induced-pluripotent-stem-cell-system\/\",\"name\":\"Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system - 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This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. 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