{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T03:11:18Z","timestamp":1772507478515,"version":"3.50.1"},"reference-count":54,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,6,1]]},"abstract":"<jats:p>NCLs (neuronal ceroid lipofuscinoses), a group of inherited neurodegenerative lysosomal storage diseases that predominantly affect children, are the result of autosomal recessive mutations within one of the nine cln genes. The wild-type cln gene products are composed of membrane and soluble proteins that localize to the lysosome or the ER (endoplasmic reticulum). However, the destiny of the Cln variants has not been fully characterized. To explore a possible link between ER quality control and processing of Cln mutants, we investigated the fate of two NCL-related Cln6 mutants found in patient samples (Cln6G123D and Cln6M241T) in neuronal-derived human cells. The point mutations are predicted to be in the putative transmembrane domains and most probably generate misfolded membrane proteins that are subjected to ER quality control. Consistent with this paradigm, both mutants underwent rapid proteasome-mediated degradation and complexed with components of the ER extraction apparatus, Derlin-1 and p97. In addition, knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a member of an E3 ubiquitin ligase complex involved in ER protein extraction, rescued significant amounts of Cln6G123D and Cln6M241T polypeptides. The results implicate ER quality control in the instability of the Cln variants that probably contributes to the development of NCL.<\/jats:p>","DOI":"10.1042\/bsr20080143","type":"journal-article","created":{"date-parts":[[2008,10,6]],"date-time":"2008-10-06T11:18:17Z","timestamp":1223291897000},"page":"173-181","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Cln6 mutants associated with neuronal ceroid lipofuscinosis are degraded in a proteasome-dependent manner"],"prefix":"10.1042","volume":"29","author":[{"given":"Kristina","family":"Oresic","sequence":"first","affiliation":[{"name":"Mount Sinai School of Medicine, Department of Microbiology, One Gustave L. 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J."},{"key":"2021111618014057700_B35","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1111\/j.1600-0854.2008.00729.x","article-title":"The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum","volume":"9","author":"Nakatsukasa","year":"2008","journal-title":"Traffic"},{"key":"2021111618014057700_B36","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1038\/414652a","article-title":"The AAA ATPase Cdc48\/p97 and its partners transport proteins from the ER into the cytosol","volume":"414","author":"Ye","year":"2001","journal-title":"Nature"},{"key":"2021111618014057700_B37","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/0092-8674(90)90148-8","article-title":"Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis","volume":"63","author":"Cheng","year":"1990","journal-title":"Cell"},{"key":"2021111618014057700_B38","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1096\/fj.04-2375com","article-title":"A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder","volume":"19","author":"Yam","year":"2005","journal-title":"FASEB J."},{"key":"2021111618014057700_B39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00439-006-0280-4","article-title":"New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy","volume":"121","author":"Beck","year":"2007","journal-title":"Hum. Genet."},{"key":"2021111618014057700_B40","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1089\/rej.2006.9.237","article-title":"Emerging strategies for the treatment of hereditary metabolic storage disorders","volume":"9","author":"Brady","year":"2006","journal-title":"Rejuvenation Res."},{"key":"2021111618014057700_B41","doi-asserted-by":"crossref","first-page":"401","DOI":"10.2174\/187152706777950738","article-title":"Molecular pathologies of and enzyme replacement therapies for lysosomal diseases","volume":"5","author":"Sakuraba","year":"2006","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"2021111618014057700_B42","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1097\/01.wco.0000084221.82329.29","article-title":"Mouse models as a tool for understanding neurodegenerative diseases","volume":"16","author":"Ahmad-Annuar","year":"2003","journal-title":"Curr. Opin. Neurol."},{"key":"2021111618014057700_B43","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.bbadis.2006.08.002","article-title":"Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis","volume":"1762","author":"Cooper","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"2021111618014057700_B44","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S1474-4422(02)00100-X","article-title":"Mouse models for neurological disease","volume":"1","author":"Hafezparast","year":"2002","journal-title":"Lancet Neurol."},{"key":"2021111618014057700_B45","doi-asserted-by":"crossref","first-page":"13566","DOI":"10.1073\/pnas.251485198","article-title":"Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice","volume":"98","author":"Gupta","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111618014057700_B46","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.nbd.2004.08.013","article-title":"Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons","volume":"18","author":"Jalanko","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"2021111618014057700_B47","doi-asserted-by":"crossref","first-page":"9117","DOI":"10.1523\/JNEUROSCI.2729-04.2004","article-title":"A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration","volume":"24","author":"Sleat","year":"2004","journal-title":"J. Neurosci."},{"key":"2021111618014057700_B48","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1093\/hmg\/ddh312","article-title":"A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging","volume":"13","author":"Kopra","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2021111618014057700_B49","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/(SICI)1096-8628(19980526)77:4<289::AID-AJMG8>3.0.CO;2-I","article-title":"Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9","volume":"77","author":"Bronson","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"2021111618014057700_B50","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1523\/JNEUROSCI.19-07-02556.1999","article-title":"Apparent loss and hypertrophy of interneurons in a mouse model of neuronal ceroid lipofuscinosis: evidence for partial response to insulin-like growth factor-1 treatment","volume":"19","author":"Cooper","year":"1999","journal-title":"J. Neurosci."},{"key":"2021111618014057700_B51","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1006\/nbdi.1999.0267","article-title":"Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. The Batten Mouse Model Consortium","volume":"6","author":"Mitchison","year":"1999","journal-title":"Neurobiol Dis."},{"key":"2021111618014057700_B52","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1093\/hmg\/11.22.2709","article-title":"Cln3(Deltaex7\/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth","volume":"11","author":"Cotman","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021111618014057700_B53","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/(SICI)1097-4547(19990815)57:4<551::AID-JNR15>3.0.CO;2-R","article-title":"A mouse gene knockout model for juvenile ceroid-lipofuscinosis (Batten disease)","volume":"57","author":"Katz","year":"1999","journal-title":"J. Neurosci. Res."},{"key":"2021111618014057700_B54","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.bbr.2005.02.024","article-title":"Behavioral assessment in mouse models of neuronal ceroid lipofuscinosis using a light-cued T-maze","volume":"161","author":"Wendt","year":"2005","journal-title":"Behav. 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