{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T22:34:35Z","timestamp":1789079675412,"version":"build-2803163510"},"reference-count":64,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Limb\u2010girdle muscular dystrophy R9 (LGMDR9) is an autosomal recessive disorder caused by mutations in the fukutin\u2010related protein gene (<jats:italic>FKRP<\/jats:italic>), encoding a glycosyltransferase involved in \u03b1\u2010dystroglycan modification. Muscle atrophy, a significant feature of LGMDR9, occurs by a change in the normal balance between protein synthesis and protein degradation. The ubiquitin\u2013proteasome system (UPS) and autophagy\u2013lysosomal system play a key role in protein degradation in skeletal muscle cells, but their involvement in the pathology of LGMDR9 is still largely unknown. We have aimed at clarifying whether proteolysis through the UPS and the autophagy\u2013lysosomal pathway is dysregulated in LGMDR9 patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>Vastus lateralis<\/jats:italic> biopsies from 8 normal controls and 12 LGMDR9 patients harbouring the c.826C&gt;A\/c.826C&gt;A <jats:italic>FKRP<\/jats:italic> genotype were assessed for protein markers related to UPS, the autophagy\u2013lysosomal system and endoplasmic reticulum (ER) stress\/unfolded protein response (UPR), followed by ultrastructural analysis by transmission electron microscopy (TEM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Protein levels of E3 ubiquitin ligases Atrogin\u20101 and MuRF1 showed a pattern similar to normal controls. Elevation of the autophagy markers Atg7, LC3B\u2010II, decreased level of p62 as well as downregulation of the negative autophagy regulator mTORC1, indicated an activation of autophagy in LGMDR9. Mitophagy markers Bnip3 and Parkin were decreased. TEM analysis demonstrated accumulation of autophagosome\u2010like structures in LGMDR9 muscle. There was also an increase in the expression of ER stress\/UPR markers PDI, peIF2\u03b1 and CHOP and a decrease in IRE1\u03b1. However, GRP94, Bip and Calnexin remained unchanged.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that autophagy and ER stress are induced in LGMDR9 muscle.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12684","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T21:42:16Z","timestamp":1608327736000},"page":"519-531","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Protein homeostasis in LGMDR9 (LGMD2I) \u2013 The role of ubiquitin\u2013proteasome and autophagy\u2013lysosomal system"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8128-0259","authenticated-orcid":false,"given":"Veronika","family":"Franekova","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine UiT The Arctic University of Norway Troms\u00f8 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