{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:08:11Z","timestamp":1772118491853,"version":"3.50.1"},"reference-count":70,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Nicotinic acetylcholine receptor (nAChR) dysregulation in astrocytes is reported in neurodegenerative disorders. Modulation of nAChRs through agonists confers protection to astrocytes from stress but regulation of chaperones involved in proteostasis with pathological implications is unclear. Resistance to inhibitors of cholinesterase 3 (\n                    <jats:italic>RIC3<\/jats:italic>\n                    ), a potential chaperone of nAChRs is poorly studied in humans. We characterized\n                    <jats:italic>RIC3<\/jats:italic>\n                    in astrocytes derived from an isogenic wild\u2010type and Cas9 edited \u201cdel\u201d human iPSC line harboring a 25\u2009bp homozygous deletion in exon2. Altered\n                    <jats:italic>RIC3<\/jats:italic>\n                    transcript ratio due to deletion induced splicing and an unexpected gain of \u03b17nAChR expression were observed in \u201cdel\u201d astrocytes. Transcriptome analysis showed higher expression of neurotransmitter\/G\u2010protein coupled receptors mediated by cAMP and calcium\/calmodulin\u2010dependent kinase signaling with increased cytokines\/glutamate secretion. Functional implications examined using tunicamycin induced ER stress in wild\u2010type astrocyte stress model showed cell cycle arrest,\n                    <jats:italic>RIC3<\/jats:italic>\n                    upregulation, reduction in \u03b17nAChR membrane levels but increased \u03b14nAChR membrane expression. Conversely, tunicamycin\u2010treated \u201cdel\u201d astrocytes showed a comparatively higher \u03b14nAChR membrane expression and upsurged cAMP signaling. Furthermore, reduced expression of stress markers CHOP, phospho\u2010PERK and lowered\n                    <jats:italic>XBP1<\/jats:italic>\n                    splicing in western blot and qPCR, validated by proteome\u2010based pathway analysis indicated lowered disease severity. Findings indicate (i) a complex RNA regulatory mechanism via exonic deletion induced splicing; (ii) RIC\u20103 as a disordered protein having contrasting effects on co\u2010expressed nAChR subtypes under basal\/stress conditions; and (iii)\n                    <jats:italic>RIC3<\/jats:italic>\n                    as a potential drug target against ER stress in astrocytes for neurodegenerative\/nicotine\u2010related brain disorders. Cellular rescue mechanism through deletion induced exon skipping may encourage ASO\u2010based therapies for tauopathies.\n                  <\/jats:p>","DOI":"10.1002\/glia.24333","type":"journal-article","created":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T06:41:55Z","timestamp":1672900915000},"page":"1217-1232","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Deletion induced splicing in\n                    <scp>\n                      <i>RIC3<\/i>\n                    <\/scp>\n                    drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes"],"prefix":"10.1002","volume":"71","author":[{"given":"Navneesh","family":"Yadav","sequence":"first","affiliation":[{"name":"Department of Genetics University of Delhi South Campus  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2154-5443","authenticated-orcid":false,"given":"B. K.","family":"Thelma","sequence":"additional","affiliation":[{"name":"Department of Genetics University of Delhi South Campus  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2008"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020506"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2013.03.007"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567205013666151218145431"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504369200"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-08-0851"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/membranes11090664"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01979-9"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/82_2017_52"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503746200"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41537-020-0105-9"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-016-0477-8"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.06.023"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13777"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00020"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10030470"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2014.12.002"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1258096"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036458"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(95)80009-Q"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.01.018"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300170200"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00507"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.08.012"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-69610-x"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2022.02.020"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.11.036"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes4030306"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0201-4"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.647040"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05235.x"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.105.017459"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20246309"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00193"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2021.729273"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.11.028"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.11.018"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchemneu.2003.08.007"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707661"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134409"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-251439"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-385114-7.00004-0"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/npjparkd.2016.1"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21458"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00187"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-016-1580-z"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1080\/09687680801960998"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20080055"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.06.008"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.036343"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14012"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24082"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.s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