{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T19:17:46Z","timestamp":1777576666017,"version":"3.51.4"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the <jats:italic>ATXN2<\/jats:italic> gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients\u2019 striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.<\/jats:p>","DOI":"10.1038\/s41419-021-04404-1","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T17:03:42Z","timestamp":1638205422000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7327-0170","authenticated-orcid":false,"given":"Adriana","family":"Marcelo","sequence":"first","affiliation":[]},{"given":"In\u00eas T.","family":"Afonso","sequence":"additional","affiliation":[]},{"given":"Ricardo","family":"Afonso-Reis","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2726-9347","authenticated-orcid":false,"given":"David V. C.","family":"Brito","sequence":"additional","affiliation":[]},{"given":"Rafael G.","family":"Costa","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Rosa","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Alves-Cruzeiro","sequence":"additional","affiliation":[]},{"given":"Benedita","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Carina","family":"Henriques","sequence":"additional","affiliation":[]},{"given":"Rui J.","family":"Nobre","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9019-7569","authenticated-orcid":false,"given":"Carlos A.","family":"Matos","sequence":"additional","affiliation":[]},{"given":"Lu\u00eds Pereira","family":"de Almeida","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8312-5292","authenticated-orcid":false,"given":"Cl\u00e9vio","family":"N\u00f3brega","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"4404_CR1","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1093\/brain\/94.2.359","volume":"94","author":"NH Wadia","year":"1971","unstructured":"Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971;94:359\u201374.","journal-title":"Brain"},{"key":"4404_CR2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/0022-510X(89)90159-7","volume":"93","author":"G Orozco","year":"1989","unstructured":"Orozco G, Estrada R, Perry TL, Ara\u00f1a J, Fernandez R, Gonzalez-Quevedo A, et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings. J Neurol Sci. 1989;93:37\u201350.","journal-title":"J Neurol Sci"},{"key":"4404_CR3","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/ng1196-269","volume":"14","author":"SM Pulst","year":"1996","unstructured":"Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinooerebellar ataxia type. Nat Genet. 1996;14:269\u201376.","journal-title":"Nat Genet"},{"key":"4404_CR4","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/ng1196-277","volume":"14","author":"K Sanpei","year":"1996","unstructured":"Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996;14:277\u201384.","journal-title":"Nat Genet"},{"key":"4404_CR5","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/s12311-008-0019-y","volume":"7","author":"I Lastres-Becker","year":"2008","unstructured":"Lastres-Becker I, R\u00fcb U, Auburger G. Spinocerebellar ataxia 2 (SCA2). Cerebellum 2008;7:115\u201324.","journal-title":"Cerebellum"},{"key":"4404_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00401-012-1000-x","volume":"124","author":"K Seidel","year":"2012","unstructured":"Seidel K, Siswanto S, Brunt ERP, Den Dunnen W, Korf HW, R\u00fcb U. Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012;124:1\u201321.","journal-title":"Acta Neuropathol"},{"key":"4404_CR7","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/s12035-012-8348-8","volume":"47","author":"JJ Maga\u00f1a","year":"2013","unstructured":"Maga\u00f1a JJ, Vel\u00e1zquez-P\u00e9rez L, Cisneros B. Spinocerebellar ataxia type 2: Clinical presentation, molecular mechanisms, and therapeutic perspectives. Mol Neurobiol 2013;47:90\u2013104.","journal-title":"Mol Neurobiol"},{"key":"4404_CR8","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.jns.2018.08.024","volume":"394","author":"A Stezin","year":"2018","unstructured":"Stezin A, Venkatesh SD, Thennarasu K, Purushottam M, Jain S, Yadav R, et al. Non-ataxic manifestations of Spinocerebellar ataxia-2, their determinants and predictors. J Neurol Sci. 2018;394:14\u201318.","journal-title":"J Neurol Sci"},{"key":"4404_CR9","doi-asserted-by":"publisher","unstructured":"Takeuchi T, Nagai Y Protein misfolding and aggregation as a therapeutic target for polyglutamine diseases. Brain Sci. 2017; 7. https:\/\/doi.org\/10.3390\/brainsci7100128.","DOI":"10.3390\/brainsci7100128"},{"key":"4404_CR10","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1080\/07391102.2016.1152199","volume":"35","author":"J Wen","year":"2017","unstructured":"Wen J, Scoles DR, Facelli JC. Effects of the enlargement of polyglutamine segments on the structure and folding of ataxin-2 and ataxin-3 proteins. J Biomol Struct Dyn. 2017;35:504\u201319.","journal-title":"J Biomol Struct Dyn"},{"key":"4404_CR11","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1111\/bpa.12412","volume":"27","author":"K Seidel","year":"2017","unstructured":"Seidel K, Siswanto S, Fredrich M, Bouzrou M, den Dunnen WFA, \u00d6zerden I, et al. On the distribution of intranuclear and cytoplasmic aggregates in the brainstem of patients with spinocerebellar ataxia type 2 and 3. Brain Pathol. 2017;27:345\u201355.","journal-title":"Brain Pathol"},{"key":"4404_CR12","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1007\/s13311-019-00777-6","volume":"16","author":"PA Egorova","year":"2019","unstructured":"Egorova PA, Bezprozvanny IB. Molecular mechanisms and therapeutics for spinocerebellar ataxia type 2. Neurotherapeutics. 2019;16:1050\u201373.","journal-title":"Neurotherapeutics"},{"key":"4404_CR13","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.mcn.2015.03.010","volume":"66","author":"CJ Cortes","year":"2015","unstructured":"Cortes CJ, La Spada AR. Autophagy in polyglutamine disease: Imposing order on disorder or contributing to the chaos? Mol Cell Neurosci 2015;66:53\u201361.","journal-title":"Mol Cell Neurosci"},{"key":"4404_CR14","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1093\/brain\/awr047","volume":"134","author":"I Nascimento-Ferreira","year":"2011","unstructured":"Nascimento-Ferreira I, Santos-Ferreira T, Sousa-Ferreira L, Auregan G, Onofre I, Alves S, et al. Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado\u2013Joseph disease. Brain. 2011;134:1400\u201315.","journal-title":"Brain"},{"key":"4404_CR15","doi-asserted-by":"publisher","unstructured":"Fujikake N, Shin M, Shimizu S Association between autophagy and neurodegenerative diseases. Front. Neurosci. 2018; 12. https:\/\/doi.org\/10.3389\/fnins.2018.00255.","DOI":"10.3389\/fnins.2018.00255"},{"key":"4404_CR16","doi-asserted-by":"publisher","unstructured":"Marcelo A, Brito F, Carmo-Silva S, Matos CA, Alves-Cruzeiro J, Vasconcelos-Ferreira A et al. Cordycepin activates autophagy through AMPK phosphorylation to reduce abnormalities in Machado\u2013Joseph disease models. Hum Mol Genet 2018. https:\/\/doi.org\/10.1093\/hmg\/ddy328.","DOI":"10.1093\/hmg\/ddy328"},{"key":"4404_CR17","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s10072-017-3156-6","volume":"39","author":"G Puorro","year":"2018","unstructured":"Puorro G, Marsili A, Sapone F, Pane C, De Rosa A, Peluso S, et al. Peripheral markers of autophagy in polyglutamine diseases. Neurol Sci. 2018;39:149\u201352.","journal-title":"Neurol Sci"},{"key":"4404_CR18","doi-asserted-by":"publisher","unstructured":"Paul S, Dansithong W, Figueroa KP, Scoles DR, Pulst SM Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration. Nat Commun 2018; 9. https:\/\/doi.org\/10.1038\/s41467-018-06041-3.","DOI":"10.1038\/s41467-018-06041-3"},{"key":"4404_CR19","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1006\/nbdi.2001.0388","volume":"8","author":"L Pereira de Almeida","year":"2001","unstructured":"Pereira de Almeida L, Zala D, Aebischer P, D\u00e9glon N. Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington\u2019s disease. Neurobiol Dis. 2001;8:433\u201346.","journal-title":"Neurobiol Dis"},{"key":"4404_CR20","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1093\/hmg\/ddg175","volume":"12","author":"DP Huynh","year":"2003","unstructured":"Huynh DP, Yang HT, Vakharia H, Nguyen D, Pulst SM. Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death. Hum Mol Genet. 2003;12:1485\u201396.","journal-title":"Hum Mol Genet"},{"key":"4404_CR21","doi-asserted-by":"publisher","first-page":"452","DOI":"10.4161\/auto.4451","volume":"3","author":"S Kimura","year":"2007","unstructured":"Kimura S, Noda T, Yoshimori T. Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy. 2007;3:452\u201360.","journal-title":"Autophagy"},{"key":"4404_CR22","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1093\/brain\/awu352","volume":"138","author":"LS Mendon\u00e7a","year":"2015","unstructured":"Mendon\u00e7a LS, N\u00f3brega C, Hirai H, Kaspar BK, Pereira de Almeida L. Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice. Brain. 2015;138:320\u201335.","journal-title":"Brain"},{"key":"4404_CR23","doi-asserted-by":"publisher","first-page":"3537","DOI":"10.1093\/brain\/awv298","volume":"138","author":"C N\u00f3brega","year":"2015","unstructured":"N\u00f3brega C, Carmo-Silva S, Albuquerque D, Vasconcelos-Ferreira A, Vijayakumar U-G, Mendon\u00e7a L, et al. Re-establishing ataxin-2 downregulates translation of mutant ataxin-3 and alleviates Machado\u2013Joseph disease. Brain. 2015;138:3537\u201354.","journal-title":"Brain"},{"key":"4404_CR24","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s12311-012-0432-0","volume":"12","author":"C N\u00f3brega","year":"2013","unstructured":"N\u00f3brega C, Nascimento-Ferreira I, Onofre I, Albuquerque D, Concei\u00e7\u00e3o M, D\u00e9glon N, et al. Overexpression of mutant ataxin-3 in mouse cerebellum induces ataxia and cerebellar neuropathology. Cerebellum. 2013;12:441\u201355.","journal-title":"Cerebellum"},{"key":"4404_CR25","doi-asserted-by":"publisher","first-page":"e100086","DOI":"10.1371\/journal.pone.0100086","volume":"9","author":"C N\u00f3brega","year":"2014","unstructured":"N\u00f3brega C, Nascimento-Ferreira I, Onofre I, Albuquerque D, D\u00e9glon N, Pereira de Almeida L. RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of Machado-Joseph disease. PLoS One. 2014;9:e100086.","journal-title":"PLoS One"},{"key":"4404_CR26","doi-asserted-by":"publisher","first-page":"9554","DOI":"10.1073\/pnas.2000671117","volume":"117","author":"JJJ Hjorth","year":"2020","unstructured":"Hjorth JJJ, Kozlov A, Carannante I, Frost Nyl\u00e9n J, Lindroos R, Johansson Y, et al. The microcircuits of striatum in silico. Proc Natl Acad Sci USA. 2020;117:9554\u201365.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4404_CR27","doi-asserted-by":"publisher","unstructured":"Alves-Cruzeiro JMDC, Mendon\u00e7a L, Pereira de Almeida L, N\u00f3brega C. Motor dysfunctions and neuropathology in mouse models of spinocerebellar ataxia type 2: a comprehensive review. Front Neurosci 2016;10. https:\/\/doi.org\/10.3389\/fnins.2016.00572.","DOI":"10.3389\/fnins.2016.00572"},{"key":"4404_CR28","doi-asserted-by":"publisher","first-page":"3473","DOI":"10.1523\/JNEUROSCI.22-09-03473.2002","volume":"22","author":"LP De Almeida","year":"2002","unstructured":"De Almeida LP, Ross CA, Zala D, Aebischer P, D\u00e9glon N. Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J Neurosci. 2002;22:3473\u201383.","journal-title":"J Neurosci"},{"key":"4404_CR29","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.1093\/hmg\/ddn106","volume":"17","author":"S Alves","year":"2008","unstructured":"Alves S, R\u00e9gulier E, Nascimento-Ferreira I, Hassig R, Dufour N, Koeppen A, et al. Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease. Hum Mol Genet. 2008;17:2071\u201383.","journal-title":"Hum Mol Genet"},{"key":"4404_CR30","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1111\/bpa.12146","volume":"24","author":"S Koyano","year":"2014","unstructured":"Koyano S, Yagishita S, Kuroiwa Y, Tanaka F, Uchihara T. Neuropathological staging of spinocerebellar ataxia type 2 by semiquantitative 1C2-positive neuron typing. Nuclear translocation of cytoplasmic 1C2 underlies disease progression of spinocerebellar ataxia type 2. Brain Pathol. 2014;24:599\u2013606.","journal-title":"Brain Pathol"},{"key":"4404_CR31","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1007\/s004010050989","volume":"97","author":"R Estrada","year":"1999","unstructured":"Estrada R, Galarraga J, Orozco G, Nodarse A, Auburger G. Spinocerebellar ataxia 2 (SCA2): Morphometric analyses in 11 autopsies. Acta Neuropathol. 1999;97:306\u201310.","journal-title":"Acta Neuropathol"},{"key":"4404_CR32","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1089\/hum.2018.157","volume":"30","author":"C N\u00f3brega","year":"2019","unstructured":"N\u00f3brega C, Cod\u00easso JM, Mendon\u00e7a L, Pereira De Almeida L. RNA interference therapy for machado-joseph disease: long-term safety profile of lentiviral vectors encoding short hairpin RNAs targeting mutant ataxin-3. Hum Gene Ther. 2019;30:841\u201354.","journal-title":"Hum Gene Ther"},{"key":"4404_CR33","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0304-3940(99)00656-4","volume":"273","author":"S Koyano","year":"1999","unstructured":"Koyano S, Uchihara T, Fujigasaki H, Nakamura A, Yagishita S, Iwabuchi K. Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: Triple-labeling immunofluorescent study. Neurosci Lett. 1999;273:117\u201320.","journal-title":"Neurosci Lett"},{"key":"4404_CR34","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1093\/brain\/awf060","volume":"125","author":"JT Pang","year":"2002","unstructured":"Pang JT, Giunti P, Chamberlain S, An SF, Vitaliani R, Scaravilli T, et al. Neuronal intranuclear inclusions in SCA2: A genetic, morphological and immunohistochemical study of two cases. Brain. 2002;125:656\u201363.","journal-title":"Brain"},{"key":"4404_CR35","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1136\/jnnp-2012-304558","volume":"85","author":"C O\u2019Callaghan","year":"2014","unstructured":"O\u2019Callaghan C, Bertoux M, Hornberger M. Beyond and below the cortex: the contribution of striatal dysfunction to cognition and behaviour in neurodegeneration. J Neurol Neurosurg Psychiatry 2014;85:371\u20138.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"4404_CR36","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.bbr.2012.04.045","volume":"233","author":"S Tanaka","year":"2012","unstructured":"Tanaka S, Young JW, Halberstadt AL, Masten VL, Geyer MA. Four factors underlying mouse behavior in an open field. Behav Brain Res. 2012;233:55\u201361.","journal-title":"Behav Brain Res"},{"key":"4404_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/cshperspect.a008656","volume":"5","author":"DR McIlwain","year":"2013","unstructured":"McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5:1\u201328.","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"4404_CR38","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1177\/41.6.8315274","volume":"41","author":"E Soriano","year":"1993","unstructured":"Soriano E, Del Rio JA, Auladell C. Characterization of the phenotype and birthdates of pyknotic dead cells in the nervous system by a combination of DNA staining and immunohistochemistry for 5\u2019-bromodeoxyuridine and neural antigens. J Histochem Cytochem. 1993;41:819\u201327.","journal-title":"J Histochem Cytochem"},{"key":"4404_CR39","doi-asserted-by":"publisher","unstructured":"Olejniczak M, Urbanek MO, Krzyzosiak WJ. The role of the immune system in triplet repeat expansion diseases. Mediators Inflamm 2015;2015. https:\/\/doi.org\/10.1155\/2015\/873860.","DOI":"10.1155\/2015\/873860"},{"key":"4404_CR40","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.5213\/inj.1632604.302","volume":"20","author":"H Hong","year":"2016","unstructured":"Hong H, Kim BS, Im H-I. Pathophysiological role of neuroinflammation in neurodegenerative diseases and psychiatric disorders. Int Neurourol J 2016;20:S2\u2013S7.","journal-title":"Int Neurourol J"},{"key":"4404_CR41","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1002\/1531-8249(199902)45:2<232::AID-ANA14>3.0.CO;2-7","volume":"45","author":"DP Huynh","year":"1999","unstructured":"Huynh DP, Del Bigio MR, Ho DH, Pulst SM. Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer\u2019s disease and spinocerebellar ataxia 2. Ann Neurol. 1999;45:232\u201341.","journal-title":"Ann Neurol"},{"key":"4404_CR42","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1111\/j.1365-2990.2007.00933.x","volume":"34","author":"F Hoche","year":"2008","unstructured":"Hoche F, Seidel K, Brunt ER, Auburger G, Sch\u00f6ls L, B\u00fcrk K, et al. Involvement of the auditory brainstem system in spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7). Neuropathol Appl Neurobiol. 2008;34:479\u201391.","journal-title":"Neuropathol Appl Neurobiol"},{"key":"4404_CR43","doi-asserted-by":"publisher","first-page":"4672","DOI":"10.1111\/febs.13540","volume":"282","author":"Y Katsuragi","year":"2015","unstructured":"Katsuragi Y, Ichimura Y, Komatsu M. P62\/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 2015;282:4672\u20138.","journal-title":"FEBS J"},{"key":"4404_CR44","doi-asserted-by":"publisher","first-page":"424","DOI":"10.5483\/BMBRep.2016.49.8.081","volume":"49","author":"YK Lee","year":"2016","unstructured":"Lee YK, Lee JA. Role of the mammalian ATG8\/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy. BMB Rep. 2016;49:424\u201330.","journal-title":"BMB Rep"},{"key":"4404_CR45","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1146\/annurev-cellbio-100818-125242","volume":"35","author":"AKH Stavoe","year":"2019","unstructured":"Stavoe AKH, Holzbaur ELF. Autophagy in neurons. Annu Rev Cell Dev Biol 2019;35:477\u2013500.","journal-title":"Annu Rev Cell Dev Biol"},{"key":"4404_CR46","doi-asserted-by":"publisher","first-page":"2523","DOI":"10.1093\/hmg\/ddl173","volume":"15","author":"TF Satterfield","year":"2006","unstructured":"Satterfield TF, Pallanck LJ. Ataxin-2 and its drosophila homolog, ATX2, physically assemble with polyribosomes. Hum Mol Genet. 2006;15:2523\u201332.","journal-title":"Hum Mol Genet"},{"key":"4404_CR47","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1385\/JMN:15:3:231","volume":"15","author":"TR Kiehl","year":"2000","unstructured":"Kiehl TR, Shibata H, Pulst SM. The ortholog of human ataxin-2 is essential for early embryonic patterning in C. elegans. J Mol Neurosci. 2000;15:231\u201341.","journal-title":"J Mol Neurosci"},{"key":"4404_CR48","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/79162","volume":"26","author":"DP Huynh","year":"2000","unstructured":"Huynh DP, Figueroa K, Hoang N, Pulst S-M. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet. 2000;26:44\u201350.","journal-title":"Nat Genet"},{"key":"4404_CR49","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.neulet.2005.09.020","volume":"392","author":"J Aguiar","year":"2006","unstructured":"Aguiar J, Fern\u00e1ndez J, Aguilar A, Mendoza Y, V\u00e1zquez M, Su\u00e1rez J, et al. Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specific Purkinje cell degeneration in transgenic mice. Neurosci Lett. 2006;392:202\u20136.","journal-title":"Neurosci Lett"},{"key":"4404_CR50","doi-asserted-by":"publisher","first-page":"e1002920","DOI":"10.1371\/journal.pgen.1002920","volume":"8","author":"E Damrath","year":"2012","unstructured":"Damrath E, Heck MV, Gispert S, Azizov M, Nowock J, Seifried C, et al. ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice. PLoS Genet. 2012;8:e1002920.","journal-title":"PLoS Genet"},{"key":"4404_CR51","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1093\/hmg\/dds427","volume":"22","author":"ST Hansen","year":"2013","unstructured":"Hansen ST, Meera P, Otis TS, Pulst SM. Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet. 2013;22:271\u201383.","journal-title":"Hum Mol Genet"},{"key":"4404_CR52","doi-asserted-by":"publisher","first-page":"e1005182","DOI":"10.1371\/journal.pgen.1005182","volume":"11","author":"W Dansithong","year":"2015","unstructured":"Dansithong W, Paul S, Figueroa KP, Rinehart MD, Wiest S, Pflieger LT, et al. Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model. PLOS Genet. 2015;11:e1005182.","journal-title":"PLOS Genet"},{"key":"4404_CR53","doi-asserted-by":"publisher","first-page":"104559","DOI":"10.1016\/j.nbd.2019.104559","volume":"132","author":"N-E Sen","year":"2019","unstructured":"Sen N-E, Canet-Pons J, Halbach MV, Arsovic A, Pilatus U, Chae W-H, et al. Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation. Neurobiol Dis. 2019;132:104559.","journal-title":"Neurobiol Dis"},{"key":"4404_CR54","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1002\/ana.20054","volume":"55","author":"A Varrone","year":"2004","unstructured":"Varrone A, Salvatore E, De Michele G, Barone P, Sansone V, Pellecchia MT, et al. Reduced striatal [123I]FP-CIT binding in SCA2 patients without Parkinsonism. Ann Neurol. 2004;55:426\u201330.","journal-title":"Ann Neurol"},{"key":"4404_CR55","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1002\/mds.10192","volume":"18","author":"W Pirker","year":"2003","unstructured":"Pirker W, Back C, Gerschlager W, Laccone F, Alesch F. Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov Disord. 2003;18:222\u20135.","journal-title":"Mov Disord"},{"key":"4404_CR56","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.expneurol.2003.09.002","volume":"185","author":"D Zala","year":"2004","unstructured":"Zala D, Bensadoun JC, De Almeida LP, Leavitt BR, Gutekunst CA, Aebischer P, et al. Long-term lentiviral-mediated expression of ciliary neurotrophic factor in the striatum of Huntington\u2019s disease transgenic mice. Exp Neurol. 2004;185:26\u201335.","journal-title":"Exp Neurol"},{"key":"4404_CR57","doi-asserted-by":"publisher","unstructured":"Fakhoury M Microglia and astrocytes in Alzheimer\u2019s disease: implications for therapy. Curr Neuropharmacol. 2017;15. https:\/\/doi.org\/10.2174\/1570159x15666170720095240.","DOI":"10.2174\/1570159x15666170720095240"},{"key":"4404_CR58","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1007\/s00401-005-1014-8","volume":"109","author":"K Gierga","year":"2005","unstructured":"Gierga K, B\u00fcrk K, Bauer M, Orozco Diaz G, Auburger G, Schultz C, et al. Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2). Acta Neuropathol. 2005;109:617\u201331.","journal-title":"Acta Neuropathol"},{"key":"4404_CR59","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/nrg2748","volume":"11","author":"AR La Spada","year":"2010","unstructured":"La Spada AR, Taylor JP. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 2010;11:247\u201358.","journal-title":"Nat Rev Genet"},{"key":"4404_CR60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms6659","volume":"5","author":"D Vilchez","year":"2014","unstructured":"Vilchez D, Saez I, Dillin A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat Commun 2014;5:1\u201313.","journal-title":"Nat Commun"},{"key":"4404_CR61","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/s12311-019-01092-8","volume":"19","author":"JH Wardman","year":"2020","unstructured":"Wardman JH, Henriksen EE, Marthaler AG, Nielsen JE, Nielsen TT. Enhancement of autophagy and solubilization of ataxin-2 alleviate apoptosis in spinocerebellar ataxia type 2 patient cells. Cerebellum. 2020;19:165\u201381.","journal-title":"Cerebellum"},{"key":"4404_CR62","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1093\/hmg\/ddaa072","volume":"29","author":"DR Scoles","year":"2020","unstructured":"Scoles DR, Dansithong W, Pflieger LT, Paul S, Gandelman M, Figueroa KP, et al. ALS-associated genes in SCA2 mouse spinal cord transcriptomes. Hum Mol Genet. 2020;29:1658\u201372.","journal-title":"Hum Mol Genet"},{"key":"4404_CR63","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1083\/jcb.200507002","volume":"171","author":"G Bj\u00f8rk\u00f8y","year":"2005","unstructured":"Bj\u00f8rk\u00f8y G, Lamark T, Brech A, Outzen H, Perander M, \u00d8vervatn A, et al. p62\/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005;171:603\u201314.","journal-title":"J Cell Biol"},{"key":"4404_CR64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2020.1797280","volume":"17","author":"DJ Klionsky","year":"2021","unstructured":"Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1. Autophagy. 2021;17:1\u2013382.","journal-title":"Autophagy"},{"key":"4404_CR65","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.cell.2005.07.002","volume":"122","author":"S Pattingre","year":"2005","unstructured":"Pattingre S, Tassa A, Qu X, Garuti R, Xiao HL, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122:927\u201339.","journal-title":"Cell"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04404-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04404-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04404-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T20:05:10Z","timestamp":1675973110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04404-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,29]]},"references-count":65,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["4404"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-04404-1","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,29]]},"assertion":[{"value":"22 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The study obtained the proper ethics consent for the work with animals as detailed in the material and methods section.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"1117"}}