{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T05:05:38Z","timestamp":1771650338765,"version":"3.50.1"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T00:00:00Z","timestamp":1590019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Grants-in-Aid for Scientific Research on Priority Areas"},{"name":"Research on Pathomechanisms of Brain Disorders","award":["17025026"],"award-info":[{"award-number":["17025026"]}]},{"name":"Protein Community","award":["20059023"],"award-info":[{"award-number":["20059023"]}]},{"name":"Synapse and Neurocircuit Pathology","award":["23110528"],"award-info":[{"award-number":["23110528"]}]},{"name":"Brain Protein Aging and Dementia Control","award":["17H05699"],"award-info":[{"award-number":["17H05699"]}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Grants-in-Aid for Scientific Research","award":["20390245"],"award-info":[{"award-number":["20390245"]}]},{"name":"Scientific Research","award":["24591287"],"award-info":[{"award-number":["24591287"]}]},{"name":"Young Scientists","award":["22790837"],"award-info":[{"award-number":["22790837"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health Labour Sciences Research Grants for Research on Development of New Drugs","award":["H24-Soyaku-Sogo-002"],"award-info":[{"award-number":["H24-Soyaku-Sogo-002"]}]},{"name":"Research for Intractable Diseases","award":["H26-Nanchi-025"],"award-info":[{"award-number":["H26-Nanchi-025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington\u2019s disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal \u03b2-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic \u03b2-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood\u2013brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.<\/jats:p>","DOI":"10.1093\/brain\/awaa115","type":"journal-article","created":{"date-parts":[[2020,3,27]],"date-time":"2020-03-27T12:09:20Z","timestamp":1585310960000},"page":"1811-1825","source":"Crossref","is-referenced-by-count":35,"title":["Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation"],"prefix":"10.1093","volume":"143","author":[{"given":"Eiko N","family":"Minakawa","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena Akiko","family":"Popiel","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"},{"name":"Division of Clinical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayoshi","family":"Tada","sequence":"first","affiliation":[{"name":"Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiaki","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Yamane","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0919-429X","authenticated-orcid":false,"given":"Yuji","family":"Saitoh","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Takahashi","sequence":"first","affiliation":[{"name":"Olympus Corporation, Hachioji, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisaku","family":"Ozawa","sequence":"first","affiliation":[{"name":"Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5005-0215","authenticated-orcid":false,"given":"Akiko","family":"Takeda","sequence":"first","affiliation":[{"name":"Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihide","family":"Takeuchi","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"},{"name":"Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuma","family":"Okamoto","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"},{"name":"Division of Clinical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"},{"name":"Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromi","family":"Fujita","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiyomi","family":"Ito","sequence":"first","affiliation":[{"name":"Division of Clinical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Yagihara","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Saito","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Watase","sequence":"first","affiliation":[{"name":"Center for Brain Integration Research, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9302-4663","authenticated-orcid":false,"given":"Hiroaki","family":"Adachi","sequence":"first","affiliation":[{"name":"Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahisa","family":"Katsuno","sequence":"first","affiliation":[{"name":"Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideki","family":"Mochizuki","sequence":"first","affiliation":[{"name":"Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kentaro","family":"Shiraki","sequence":"first","affiliation":[{"name":"Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gen","family":"Sobue","sequence":"first","affiliation":[{"name":"Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5718-2824","authenticated-orcid":false,"given":"Tatsushi","family":"Toda","sequence":"first","affiliation":[{"name":"Division of Clinical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiji","family":"Wada","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osamu","family":"Onodera","sequence":"first","affiliation":[{"name":"Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitaka","family":"Nagai","sequence":"first","affiliation":[{"name":"Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan"},{"name":"Division of Clinical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"},{"name":"Department of Neurotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"},{"name":"Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,5,21]]},"reference":[{"key":"2020062714334553000_OP-B1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S0006-291X(03)00578-3","article-title":"The effects of arginine on refolding of aggregated proteins: not facilitate refolding, but suppress aggregation","volume":"304","author":"Arakawa","year":"2003","journal-title":"Biochem Biophys Res Commun"},{"key":"2020062714334553000_OP-B2","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41582-018-0051-6","article-title":"Spinocerebellar ataxias: prospects and challenges for therapy development","volume":"14","author":"Ashizawa","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"2020062714334553000_OP-B3","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1111\/j.1471-4159.2009.06302.x","article-title":"The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies","volume":"110","author":"Bauer","year":"2009","journal-title":"J Neurochem"},{"key":"2020062714334553000_OP-B4","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nn.3028","article-title":"The toxic A\u03b2 oligomer and Alzheimer\u2019s disease: an emperor in need of clothes","volume":"15","author":"Benilova","year":"2012","journal-title":"Nat Neurosci"},{"key":"2020062714334553000_OP-B5","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1007\/s10545-012-9494-x","article-title":"Creatine metabolism in urea cycle defects","volume":"35","author":"Boenzi","year":"2012","journal-title":"J Inherit Metab Dis"},{"key":"2020062714334553000_OP-B6","doi-asserted-by":"crossref","first-page":"7597","DOI":"10.1523\/JNEUROSCI.0990-06.2006","article-title":"Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model","volume":"26","author":"Brignull","year":"2006","journal-title":"J Neurosci"},{"key":"2020062714334553000_OP-B7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1006\/jmbi.2001.4850","article-title":"Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity1","volume":"311","author":"Chen","year":"2001","journal-title":"J Mol Biol"},{"key":"2020062714334553000_OP-B8","doi-asserted-by":"crossref","first-page":"4860","DOI":"10.1016\/j.bbagen.2013.06.029","article-title":"Inhibiting toxic aggregation of amyloidogenic proteins: a therapeutic strategy for protein misfolding diseases","volume":"1830","author":"Cheng","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"2020062714334553000_OP-B9","doi-asserted-by":"crossref","first-page":"16685","DOI":"10.1073\/pnas.0707842104","article-title":"A small-molecule therapeutic lead for Huntington\u2019s disease: preclinical pharmacology and efficacy of C2-8 in the R6\/2 transgenic mouse","volume":"104","author":"Chopra","year":"2007","journal-title":"Proc 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