{"id":35662,"date":"2024-05-24T11:10:22","date_gmt":"2024-05-24T09:10:22","guid":{"rendered":"https:\/\/irb.usi.ch\/?p=35662"},"modified":"2024-05-24T11:10:22","modified_gmt":"2024-05-24T09:10:22","slug":"new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases","status":"publish","type":"post","link":"https:\/\/irb.usi.ch\/it\/news\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\/","title":{"rendered":"New Study Reveals Alternative Pathways for Clearing Misfolded Proteins in Rare Diseases"},"content":{"rendered":"<p><strong>Rare diseases like the deficiency of alpha1-antitrypsin or lysosomal storage disorders are caused by degradation of mutant proteins. In their latest study published in EMBO Reports, Elisa Fasana, Ilaria Fregno, Carmela Galli and Tatiana Sold\u00e0 in the group led by Maurizio Molinari elucidate the pathways that ensure the clearance of misfolded proteins, when the major cellular clearance pathway, the ubiquitin-proteasome system, is dysfunctional. \u00a0<\/strong><\/p>\n<p>Bellinzona, May 23, 2024\u00a0\u2013 Proteins produced in the endoplasmic reticulum (ER) of our cells are assisted by molecular chaperones and are offered a given time to complete their folding program. If folding fails or is too slow as it happens in mutant proteins linked to rare \u201cprotein misfolding diseases\u201d, the polypeptide chain is degraded. It is important to establish the mechanisms regulating protein degradation from the ER because their inhibition prolongs the time available to nascent polypeptides to attain the native structure thus increasing the fraction of functional proteins produced by the cells. On the contrary, their enhancement facilitates removal of misfolded or aged polypeptides that would otherwise accumulate in our cells. Normally, misfolded proteins are exported from the ER into the cytoplasm, where they are poly-ubiquitylated and degraded by 26S-proteasomes in catabolic processes collectively defined as ER-associated degradation (ERAD).<\/p>\n<p>Our team examined the fate of misfolded proteins in cells with dysfunctional ERAD upon pharmacologic inactivation of sugar processing enzymes that determine the time allocated to polypeptides to attain the native structure, upon inhibition of 26S-proteasomes, or upon elimination of various ERAD regulators by CRISPR-Cas9 genome editing. Our experiments show that ERAD dysfunction is compensated by the activation of alternative pathways that regulate segregation of misfolded polypeptides in ER subdomains. These eventually deliver their content to lysosomal compartments for clearance by mechanisms that we have named ER-to-lysosome-associated degradation (ERLAD). ERLAD involves luminal molecular chaperones like calnexin, ER-phagy receptors like FAM134B and autophagy gene products like LC3.<\/p>\n<p>The work in our group is supported by the Swiss National Science Foundation and by Eurostar.<\/p>\n<p><a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/38773321\/\">Link to the Scientific Article\u00a0<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Rare diseases like the deficiency of alpha1-antitrypsin or lysosomal storage disorders are caused by degradation of mutant proteins. In their latest study published in EMBO Reports, Elisa Fasana, Ilaria Fregno, Carmela Galli and Tatiana Sold\u00e0 in the group led by Maurizio Molinari elucidate the pathways that ensure the clearance of misfolded proteins, when the major [&hellip;]<\/p>\n","protected":false},"author":140,"featured_media":35660,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":""},"categories":[16],"tags":[],"class_list":["post-35662","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.6 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>New Study Reveals Alternative Pathways for Clearing Misfolded Proteins in Rare Diseases - IRB USI<\/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:\/\/irb.usi.ch\/it\/news\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\/\" \/>\n<meta property=\"og:locale\" content=\"it_IT\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"New Study Reveals Alternative Pathways for Clearing Misfolded Proteins in Rare Diseases - IRB USI\" \/>\n<meta property=\"og:description\" content=\"Rare diseases like the deficiency of alpha1-antitrypsin or lysosomal storage disorders are caused by degradation of mutant proteins. In their latest study published in EMBO Reports, Elisa Fasana, Ilaria Fregno, Carmela Galli and Tatiana Sold\u00e0 in the group led by Maurizio Molinari elucidate the pathways that ensure the clearance of misfolded proteins, when the major [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/irb.usi.ch\/it\/news\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\/\" \/>\n<meta property=\"og:site_name\" content=\"IRB USI\" \/>\n<meta property=\"article:published_time\" content=\"2024-05-24T09:10:22+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/irb.usi.ch\/images\/FOTOMMO.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"2357\" \/>\n\t<meta property=\"og:image:height\" content=\"1312\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Viviana Granelli\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Scritto da\" \/>\n\t<meta name=\"twitter:data1\" content=\"Viviana Granelli\" \/>\n\t<meta name=\"twitter:label2\" content=\"Tempo di lettura stimato\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minuti\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/news\\\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/news\\\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\\\/\"},\"author\":{\"name\":\"Viviana Granelli\",\"@id\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/#\\\/schema\\\/person\\\/e3529a53127a78cf8ead39a83c87f29b\"},\"headline\":\"New Study Reveals Alternative Pathways for Clearing Misfolded Proteins in Rare Diseases\",\"datePublished\":\"2024-05-24T09:10:22+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/news\\\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\\\/\"},\"wordCount\":342,\"publisher\":{\"@id\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/#organization\"},\"image\":{\"@id\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/news\\\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/irb.usi.ch\\\/images\\\/FOTOMMO.jpg\",\"articleSection\":[\"News\"],\"inLanguage\":\"it-IT\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/news\\\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\\\/\",\"url\":\"https:\\\/\\\/irb.usi.ch\\\/it\\\/news\\\/new-study-reveals-alternative-pathways-for-clearing-misfolded-proteins-in-rare-diseases\\\/\",\"name\":\"New Study Reveals Alternative Pathways for Clearing Misfolded Proteins in Rare Diseases - 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