{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:28:56Z","timestamp":1791322136560,"version":"4.3.1"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Biallelic variants in\n                      <jats:italic>PRKN<\/jats:italic>\n                      cause autosomal recessive Parkinson's disease (PD) with a median age at onset of 31\u2009years. When evaluating the 16 previously published carriers of a homozygous deletion of Exon 2 from the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) database, the median age at onset is later (39.5\u2009years) than in carriers of other\n                      <jats:italic>PRKN<\/jats:italic>\n                      pathogenic variants. We investigated whether these carriers show delayed disease onset compared with carriers of other pathogenic\n                      <jats:italic>PRKN<\/jats:italic>\n                      variants and explored the underlying molecular mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We compared 26 homozygous\n                      <jats:italic>PRKN<\/jats:italic>\n                      Exon 2 deletion carriers with carriers of other pathogenic variants. Using human\u2010induced pluripotent stem cell (hiPSC)\u2010derived neuronal cell models from an unaffected 86\u2010year\u2010old carrier, genome\u2010edited control lines, neuroblastoma cell lines, and in silico prediction, we investigated the underlying mechanism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients with\n                      <jats:italic>PRKN<\/jats:italic>\n                      Exon 2 deletions showed a later age at onset compared with carriers of other pathogenic variants. We discovered elevated levels of an N\u2010terminally truncated Parkin proteoform lacking amino acids 1\u201379 due to internal translation initiation. This truncated protein partially retained ubiquitin ligase activity at endogenous levels. Treatment with Parkin modulator BIO\u20102007817 enhanced this residual function but reduced endogenous full\u2010length Parkin activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Residual truncated Parkin function provides a molecular explanation for a delayed disease onset in\n                      <jats:italic>PRKN<\/jats:italic>\n                      Exon 2 deletion carriers. Whereas this retained activity can be pharmacologically enhanced, the modulator's inhibitory effect on endogenous full\u2010length Parkin may mandate strict patient stratification based on genotype. This finding offers mutation\u2010specific counseling opportunities and highlights a potential therapeutic approach for appropriately selected patients with PARK\u2010\n                      <jats:italic>PRKN<\/jats:italic>\n                      . ANN NEUROL 2026;99:1379\u20131393\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78180","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T04:00:21Z","timestamp":1771819221000},"page":"1379-1393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Alternative Translation Initiation in\n                    <scp>\n                      <i>PRKN<\/i>\n                    <\/scp>\n                    Delays the Onset of Parkinson's Disease and Offers a Therapeutic Target"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7557-2391","authenticated-orcid":false,"given":"Arian","family":"Hach","sequence":"first","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck  L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Lohmann","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck  L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Funayama","sequence":"additional","affiliation":[{"name":"Research Institute for Diseases of Old Age, Graduate School of Medicine Juntendo University  Tokyo Japan"},{"name":"Department of Neurology Faculty of Medicine, Juntendo University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poornima J.","family":"Menon","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau \u2013 Paris Brain Institute \u2013 ICM, Inserm, CNRS Department of Neurology, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva\u2010Juliane","family":"Vollstedt","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck  L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Kleinz","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck  L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyo","family":"Yoshino","sequence":"additional","affiliation":[{"name":"Research Institute for Diseases of Old Age, Graduate School of Medicine Juntendo University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Lesage","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau \u2013 Paris Brain Institute \u2013 ICM, Inserm, CNRS Department of Neurology, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"Meier","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck  L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Sue","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of New South Wales  Sydney Australia"},{"name":"Neuroscience Research Australia  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Christophe","family":"Corvol","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau \u2013 Paris Brain Institute \u2013 ICM, Inserm, CNRS Department of Neurology, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Brice","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau \u2013 Paris Brain Institute \u2013 ICM, Inserm, CNRS Department of Neurology, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobutaka","family":"Hattori","sequence":"additional","affiliation":[{"name":"Research Institute for Diseases of Old Age, Graduate School of Medicine Juntendo University  Tokyo Japan"},{"name":"Neurodegenerative Disorders Collaborative Laboratory RIKEN Center for Brain Science  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck  L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar","family":"Rakovic","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck  L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,22]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae142"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae188"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwg068"},{"key":"e_1_2_9_5_1","volume-title":"GeneReviews\u00ae","author":"Br\u00fcggemann N","year":"1993"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27352"},{"key":"e_1_2_9_7_1","unstructured":"MDSGene2025Accessed February 28 2025. Available at:https:\/\/mdsgene.org\/"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-024-00677-3"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-018-0219-z"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200809125"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000298"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200910140"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016746"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi292"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000605"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52534-6"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14697"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021109460"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)61113-3"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02854.x"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5537-06.2007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25041"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51889-3"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103650"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa167"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/neup.12735"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.12.014"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0292180"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10648"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx132"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.060"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nargab\/lqad021"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.01.036"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-31531-w"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep44373"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45829-4"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu244"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.204"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12043"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep01002"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-018-0088-7"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42876-1"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20272"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000171859.85078.3d"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21062"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-010-5485-8"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/473640"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26845"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78180","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.78180","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78180","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T05:24:22Z","timestamp":1779773062000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.78180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,22]]},"references-count":47,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/ana.78180"],"URL":"https:\/\/doi.org\/10.1002\/ana.78180","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,22]]},"assertion":[{"value":"2025-09-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}