{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T03:43:58Z","timestamp":1788493438275,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T00:00:00Z","timestamp":1678752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MJD Foundation","award":["APP1069235"],"award-info":[{"award-number":["APP1069235"]}]},{"name":"MJD Foundation","award":["APP1146750"],"award-info":[{"award-number":["APP1146750"]}]},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["APP1069235"],"award-info":[{"award-number":["APP1069235"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["APP1146750"],"award-info":[{"award-number":["APP1146750"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Spinocerebellar ataxia 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3\/MJD gene. The presence of this genetic expansion results in an ataxin-3 protein containing a polyglutamine repeat region, which renders the ataxin-3 protein aggregation prone. Formation of ataxin-3 protein aggregates is linked with neuronal loss and, therefore, the development of motor deficits. Methods: Here, we investigated whether the autophagy protein quality control pathway, which is important in the process of protein aggregate removal, is impaired in a cell culture and zebrafish model of SCA3. Results: We found that SH-SY5Y cells expressing human ataxin-3 containing polyglutamine expansion exhibited aberrant levels of autophagy substrates, including increased p62 and decreased LC3II (following bafilomycin treatment), compared to the controls. Similarly, transgenic SCA3 zebrafish showed signs of autophagy impairment at early disease stages (larval), as well as p62 accumulation at advanced age stages (18 months old). We then examined whether treating with compounds known to induce autophagy activity, would aid removal of human ataxin-3 84Q and improve the swimming of the SCA3 zebrafish larvae. We found that treatment with loperamide, trehalose, rapamycin, and MG132 each improved the swimming of the SCA3 zebrafish compared to the vehicle-treated controls. Conclusion: We propose that signs of autophagy impairment occur in the SH-SY5Y model of SCA3 and SCA3 zebrafish at larval and advanced age stages. Treatment of the larval SCA3 zebrafish with various compounds with autophagy induction capacity was able to produce the improved swimming of the zebrafish, suggesting the potential benefit of autophagy-inducing compounds for the treatment of SCA3.<\/jats:p>","DOI":"10.3390\/cells12060893","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T06:36:36Z","timestamp":1678862196000},"page":"893","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Autophagy Function and Benefits of Autophagy Induction in Models of Spinocerebellar Ataxia Type 3"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8400-4994","authenticated-orcid":false,"given":"Maxinne","family":"Watchon","sequence":"first","affiliation":[{"name":"Center for MND Research, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luan","family":"Luu","sequence":"additional","affiliation":[{"name":"Center for MND Research, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart K.","family":"Plenderleith","sequence":"additional","affiliation":[{"name":"Center for MND Research, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy C.","family":"Yuan","sequence":"additional","affiliation":[{"name":"Center for MND Research, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela S.","family":"Laird","sequence":"additional","affiliation":[{"name":"Center for MND Research, Macquarie Medical School, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00441-004-0956-9","article-title":"Stages in the development of Parkinson\u2019s disease-related pathology","volume":"318","author":"Braak","year":"2004","journal-title":"Cell. Tissue Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"314","author":"Neumann","year":"2006","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.pneurobio.2013.01.001","article-title":"Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7","volume":"104","author":"Rub","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3592","DOI":"10.1523\/JNEUROSCI.5167-03.2004","article-title":"Oligomerization of Alzheimer\u2019s beta-amyloid within processes and synapses of cultured neurons and brain","volume":"24","author":"Takahashi","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1097\/00001756-200604240-00022","article-title":"Aggregate distribution in frontal and motor cortex in Huntington\u2019s disease brain","volume":"17","author":"Hogg","year":"2006","journal-title":"Neuroreport"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/cdd.2014.204","article-title":"Autophagy in the physiology and pathology of the central nervous system","volume":"22","author":"Nikoletopoulou","year":"2015","journal-title":"Cell. Death Differ."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Lin, S.Y., Liu, J.W., Lin, S.Z., Harn, H.J., and Chiou, T.W. (2021). n-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126339"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2174\/1871527314666150821101522","article-title":"Novel Lactulose and Melibiose Targeting Autophagy to Reduce PolyQ Aggregation in Cell Models of Spinocerebellar Ataxia 3","volume":"15","author":"Lin","year":"2016","journal-title":"CNS Neurol. Disord. Drug. Targets"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/hmg\/ddy328","article-title":"Cordycepin activates autophagy through AMPK phosphorylation to reduce abnormalities in Machado-Joseph disease models","volume":"28","author":"Marcelo","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6701793","DOI":"10.1155\/2016\/6701793","article-title":"Autophagy Promoted the Degradation of Mutant ATXN3 in Neurally Differentiated Spinocerebellar Ataxia-3 Human Induced Pluripotent Stem Cells","volume":"2016","author":"Ou","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Robinson, K.J., Yuan, K., Plenderleith, S.K., Watchon, M., and Laird, A.S. (2021). A Novel Calpain Inhibitor Compound Has Protective Effects on a Zebrafish Model of Spinocerebellar Ataxia Type 3. Cells, 10.","DOI":"10.3390\/cells10102592"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1186\/s12967-020-02302-2","article-title":"Trehalose alleviates the phenotype of Machado-Joseph disease mouse models","volume":"18","author":"Santana","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e12763","DOI":"10.1111\/nan.12763","article-title":"The autophagy-enhancing drug carbamazepine improves neuropathology and motor impairment in mouse models of Machado-Joseph disease","volume":"48","author":"Codesso","year":"2022","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7782","DOI":"10.1523\/JNEUROSCI.1142-17.2017","article-title":"Calpain Inhibition Is Protective in Machado-Joseph Disease Zebrafish Due to Induction of Autophagy","volume":"37","author":"Watchon","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.freeradbiomed.2017.12.011","article-title":"Caffeic acid and resveratrol ameliorate cellular damage in cell and Drosophila models of spinocerebellar ataxia type 3 through upregulation of Nrf2 pathway","volume":"115","author":"Wu","year":"2018","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_16","first-page":"54","article-title":"Correlation between CAG repeat length and clinical features in Machado-Joseph disease","volume":"57","author":"Maciel","year":"1995","journal-title":"Am. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/0022-510X(96)00016-0","article-title":"The relationship between trinucleotide repeat length and phenotypic variation in Machado-Joseph disease","volume":"139","author":"Matsumura","year":"1996","journal-title":"J. Neurol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.neulet.2012.06.026","article-title":"Autophagy-related proteins (p62, NBR1 and LC3) in intranuclear inclusions in neurodegenerative diseases","volume":"522","author":"Mori","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1093\/brain\/awr047","article-title":"Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease","volume":"134","author":"Auregan","year":"2011","journal-title":"Brain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/neup.12433","article-title":"Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients","volume":"38","author":"Sittler","year":"2018","journal-title":"Neuropathology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"28220","DOI":"10.1038\/srep28220","article-title":"Fibroblasts of Machado Joseph Disease patients reveal autophagy impairment","volume":"6","author":"Onofre","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.neuroscience.2015.11.030","article-title":"Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease","volume":"313","author":"Maciel","year":"2016","journal-title":"Neuroscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/brain\/awp292","article-title":"Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3","volume":"133","author":"Menzies","year":"2010","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2020.1797280","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy","volume":"17","author":"Klionsky","year":"2021","journal-title":"Autophagy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.4155\/fmc.12.112","article-title":"Modulating macroautophagy: A neuronal perspective","volume":"4","author":"Johnson","year":"2012","journal-title":"Future Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nchembio.79","article-title":"Novel targets for Huntington\u2019s disease in an mTOR-independent autophagy pathway","volume":"4","author":"Williams","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1080\/15548627.2018.1535292","article-title":"Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration","volume":"15","author":"Rusmini","year":"2019","journal-title":"Autophagy"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Romero-Granados, R., Fontan-Lozano, A., Aguilar-Montilla, F.J., and Carrion, A.M. (2011). Postnatal proteasome inhibition induces neurodegeneration and cognitive deficiencies in adult mice: A new model of neurodevelopment syndrome. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028927"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"513","DOI":"10.2353\/ajpath.2007.070188","article-title":"Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability","volume":"171","author":"Ding","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"170","DOI":"10.3389\/fcell.2019.00170","article-title":"Proteasome Inhibition Activates Autophagy-Lysosome Pathway Associated With TFEB Dephosphorylation and Nuclear Translocation","volume":"7","author":"Li","year":"2019","journal-title":"Front. Cell. Dev. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"643","DOI":"10.4161\/auto.5050","article-title":"HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration","volume":"3","author":"Pandey","year":"2007","journal-title":"Autophagy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1042\/EBC20170021","article-title":"The mammalian ULK1 complex and autophagy initiation","volume":"61","author":"Zachari","year":"2017","journal-title":"Essays Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.ymthe.2021.07.012","article-title":"ULK overexpression mitigates motor deficits and neuropathology in mouse models of Machado-Joseph disease","volume":"30","author":"Martins","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1080\/15548627.2016.1183843","article-title":"The circadian clock regulates autophagy directly through the nuclear hormone receptor Nr1d1\/Rev-erbalpha and indirectly via Cebpb\/(C\/ebpbeta) in zebrafish","volume":"12","author":"Huang","year":"2016","journal-title":"Autophagy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-1-59745-157-4_4","article-title":"LC3 and Autophagy","volume":"445","author":"Tanida","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1159\/000228892","article-title":"Zebrafish as a genetic model in biological and behavioral gerontology: Where development meets aging in vertebrates--a mini-review","volume":"55","author":"Kishi","year":"2009","journal-title":"Gerontology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.4161\/auto.28784","article-title":"Pathogenic role of BECN1\/Beclin 1 in the development of amyotrophic lateral sclerosis","volume":"10","author":"Nassif","year":"2014","journal-title":"Autophagy"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/aps.2012.14","article-title":"The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1","volume":"33","author":"Wu","year":"2012","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1007\/s13238-010-0048-4","article-title":"Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis","volume":"1","author":"Zhu","year":"2010","journal-title":"Protein Cell."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1093\/brain\/awt144","article-title":"Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease","volume":"136","author":"Nobrega","year":"2013","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s13041-021-00839-x","article-title":"Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo","volume":"14","author":"Watchon","year":"2021","journal-title":"Mol. Brain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"431","DOI":"10.4161\/auto.27344","article-title":"Expression of the autophagy substrate SQSTM1\/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids","volume":"10","author":"Sahani","year":"2014","journal-title":"Autophagy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1007\/s12311-020-01150-6","article-title":"Trehalose in Machado-Joseph Disease: Safety, Tolerability, and Efficacy","volume":"19","author":"Zaltzman","year":"2020","journal-title":"Cerebellum"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19023","DOI":"10.1073\/pnas.0709695104","article-title":"Small molecule regulators of autophagy identified by an image-based high-throughput screen","volume":"104","author":"Zhang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"E803","DOI":"10.1503\/cmaj.161421","article-title":"Loperamide abuse","volume":"189","author":"Antoniou","year":"2017","journal-title":"CMAJ"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/6\/893\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:54:54Z","timestamp":1760122494000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/6\/893"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,14]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["cells12060893"],"URL":"https:\/\/doi.org\/10.3390\/cells12060893","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,14]]}}}