{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:51:56Z","timestamp":1764787916113,"version":"3.46.0"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 112-2314-B-075-039- and 113-2314-B-075-073-MY3"],"award-info":[{"award-number":["NSTC 112-2314-B-075-039- and 113-2314-B-075-073-MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["111-2320-B-002-049-MY3, 112-2314-B-002-016, and 113-2320-B002-022-MY3"],"award-info":[{"award-number":["111-2320-B-002-049-MY3, 112-2314-B-002-016, and 113-2320-B002-022-MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["113-2636-B-006-006"],"award-info":[{"award-number":["113-2636-B-006-006"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["EX112-11228NI and EX113-11228NI"],"award-info":[{"award-number":["EX112-11228NI and EX113-11228NI"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006477","name":"National Taiwan University","doi-asserted-by":"publisher","award":["112L895403 and 113L893103"],"award-info":[{"award-number":["112L895403 and 113L893103"]}],"id":[{"id":"10.13039\/501100006477","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Spinocerebellar ataxia type 36 (SCA36) is a neurodegenerative disease caused by expanded (GGCCTG)n hexanucleotide repeat sequence in the\n                    <jats:italic>NOP56<\/jats:italic>\n                    gene. While the expanded repeats could transcribe and form toxic RNA foci within neurons, recent evidence indicates that translation of these repeats produces dipeptide repeats (DPR) that contribute to neurotoxicity. The relative impact of hexanucleotide RNA repeats (HRR) and DPR on the neurodegeneration of SCA36 remains unclear. Here, we established a\n                    <jats:italic>Drosophila<\/jats:italic>\n                    SCA36 model to dissect the neurotoxic effects of HRR and DPR. The fly model recapitulates the cellular defects observed in SCA36 patient fibroblasts, validating its relevance for mechanistic study of SCA36. Further engineering the transgenes to express individual DPRs reveal Proline-Glycine-DPR (PG-DPR) as the most potent neurotoxin causing progressive motor and sensory dysfunction. Expressing a series of the SCA36 transgenes with varying HRR lengths demonstrates an age- and length-dependent adult-onset neurodegeneration. Interestingly, sequence modification of the transgenes to exclusively express HRR or DPR alone causes a milder phenotype, indicating both HRR and DPR contribute partially to the pathogenicity of SCA36. Therefore, this model provides a valuable platform for screening drug targeting either HRR- or DPR-mediated toxicity of SCA36. Suppression of the RNA elongation factor\n                    <jats:italic>SUPT4H1<\/jats:italic>\n                    ortholog reduces RNA foci in cell culture. However, expression level of\n                    <jats:italic>SUPT4H1<\/jats:italic>\n                    was not changed in SCA36 patient cells. Interestingly, knockdown of the\n                    <jats:italic>Drosophila SUPT4H1<\/jats:italic>\n                    ortholog or 6-azauridine treatment to suppress RNA transcription aggravates the neurodegenerative phenotypes in both the fly models and patient-derived fibroblasts, highlighting the complex interplay of pathomechanisms in SCA36. These results underscore the need for carefully evaluating the potential side effects when designing therapeutic interventions for SCA36.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011954","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:40:02Z","timestamp":1764787202000},"page":"e1011954","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A fly model of SCA36 reveals combinatorial neurotoxicity of hexanucleotide and dipeptide repeats"],"prefix":"10.1371","volume":"21","author":[{"given":"Cheng-Tsung","family":"Hsiao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ssu-Ju","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting-Ni","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Chi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Jung","family":"Tsao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenying","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Chu","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2176-657X","authenticated-orcid":true,"given":"Masayuki","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Yi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-164X","authenticated-orcid":true,"given":"Yi-Chung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0337-4473","authenticated-orcid":true,"given":"Chien-Hung","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2626-3805","authenticated-orcid":true,"given":"Chih-Chiang","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"issue":"1","key":"pgen.1011954.ref001","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ajhg.2011.05.015","article-title":"Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement","volume":"89","author":"H Kobayashi","year":"2011","journal-title":"Am J Hum Genet"},{"key":"pgen.1011954.ref002","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1093\/brain\/aws069","article-title":"\u201cCosta da Morte\u201d ataxia is spinocerebellar ataxia 36: clinical and genetic characterization","volume":"135","author":"M Garc\u00eda-Murias","year":"2012","journal-title":"Brain"},{"issue":"4","key":"pgen.1011954.ref003","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1212\/WNL.0b013e318260436f","article-title":"Clinical features of SCA36: a novel spinocerebellar ataxia with motor neuron involvement (Asidan)","volume":"79","author":"Y Ikeda","year":"2012","journal-title":"Neurology"},{"issue":"9","key":"pgen.1011954.ref004","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1136\/jnnp-2014-309153","article-title":"Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion","volume":"86","author":"M Obayashi","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"5","key":"pgen.1011954.ref005","article-title":"Repeat expansions in NOP56 are a cause of spinocerebellar ataxia Type 36 in the British population","volume":"5","author":"T Lam","year":"2023","journal-title":"Brain Commun"},{"issue":"3","key":"pgen.1011954.ref006","article-title":"Spinocerebellar ataxia type 36 in the Han Chinese","volume":"2","author":"Y-C Lee","year":"2016","journal-title":"Neurol Genet"},{"issue":"2","key":"pgen.1011954.ref007","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1111\/cge.12706","article-title":"Genetic and clinical analysis of spinocerebellar ataxia type 36 in Mainland China","volume":"90","author":"S Zeng","year":"2016","journal-title":"Clin Genet"},{"issue":"4","key":"pgen.1011954.ref008","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000000174","article-title":"Prevalence of spinocerebellar ataxia 36 in a US population","volume":"3","author":"JM Valera","year":"2017","journal-title":"Neurol Genet"},{"issue":"9","key":"pgen.1011954.ref009","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1002\/mds.28105","article-title":"Rapid diagnosis of spinocerebellar ataxia 36 in a three-generation family using short-read whole-genome sequencing data","volume":"35","author":"H Rafehi","year":"2020","journal-title":"Mov Disord"},{"key":"pgen.1011954.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/cjn.2024.335","article-title":"Rare spinocerebellar ataxia types in Canada: a case series and review of the literature","author":"S Alshimemeri","year":"2024","journal-title":"Can J Neurol Sci"},{"key":"pgen.1011954.ref011","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.omtn.2017.06.017","article-title":"Antisense oligonucleotides reduce RNA foci in spinocerebellar ataxia 36 patient iPSCs","volume":"8","author":"K Matsuzono","year":"2017","journal-title":"Mol Ther Nucleic Acids"},{"key":"pgen.1011954.ref012","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.brainres.2018.12.045","article-title":"Suppression of the yeast elongation factor Spt4 ortholog reduces expanded SCA36 GGCCUG repeat aggregation and cytotoxicity","volume":"1711","author":"N Furuta","year":"2019","journal-title":"Brain Res"},{"issue":"4","key":"pgen.1011954.ref013","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.cell.2011.12.032","article-title":"Spt4 is selectively required for transcription of extended trinucleotide repeats","volume":"148","author":"C-R Liu","year":"2012","journal-title":"Cell"},{"issue":"6300","key":"pgen.1011954.ref014","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1126\/science.aaf7791","article-title":"Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts","volume":"353","author":"NJ Kramer","year":"2016","journal-title":"Science"},{"issue":"1","key":"pgen.1011954.ref015","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s40478-018-0564-7","article-title":"Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease","volume":"6","author":"N Sakae","year":"2018","journal-title":"Acta Neuropathol Commun"},{"issue":"2","key":"pgen.1011954.ref016","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuron.2020.04.011","article-title":"Chimeric peptide species contribute to divergent dipeptide repeat pathology in c9ALS\/FTD and SCA36","volume":"107","author":"ZT 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Mizielinska","year":"2014","journal-title":"Science"},{"issue":"3","key":"pgen.1011954.ref032","article-title":"Effects on murine behavior and lifespan of selectively decreasing expression of mutant huntingtin allele by supt4h knockdown","volume":"11","author":"H-M Cheng","year":"2015","journal-title":"PLoS Genet"},{"issue":"9","key":"pgen.1011954.ref033","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S1474-4422(24)00216-3","article-title":"Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study","volume":"23","author":"LH van den Berg","year":"2024","journal-title":"Lancet Neurol"},{"issue":"13","key":"pgen.1011954.ref034","doi-asserted-by":"crossref","first-page":"109755","DOI":"10.1016\/j.celrep.2021.109755","article-title":"Spt4 facilitates the movement of RNA polymerase II through the +2 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Maharjan","year":"2020","journal-title":"Neuron"},{"issue":"8","key":"pgen.1011954.ref038","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.3390\/biomedicines10081814","article-title":"A nop56 zebrafish loss-of-function model exhibits a severe neurodegenerative phenotype","volume":"10","author":"A Quelle-Regaldie","year":"2022","journal-title":"Biomedicines"}],"container-title":["PLOS 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