{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T06:08:06Z","timestamp":1777270086905,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T00:00:00Z","timestamp":1665100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Science and Technology Foundation (FCT) project","award":["ALG-01-0145-FEDER-29480"],"award-info":[{"award-number":["ALG-01-0145-FEDER-29480"]}]},{"name":"Portuguese Science and Technology Foundation (FCT) project","award":["22424"],"award-info":[{"award-number":["22424"]}]},{"DOI":"10.13039\/100007393","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["ALG-01-0145-FEDER-29480"],"award-info":[{"award-number":["ALG-01-0145-FEDER-29480"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007393","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["22424"],"award-info":[{"award-number":["22424"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1\/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.<\/jats:p>","DOI":"10.3390\/ijms231911896","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T23:39:31Z","timestamp":1665272371000},"page":"11896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mutant Ataxin-2 Expression in Aged Animals Aggravates Neuropathological Features Associated with Spinocerebellar Ataxia Type 2"],"prefix":"10.3390","volume":"23","author":[{"given":"In\u00eas T.","family":"Afonso","sequence":"first","affiliation":[{"name":"Algarve Biomedical Center\u2013Research Institute, 8005-139 Faro, Portugal"},{"name":"Faculdade de Medicina e Ci\u00eancias Biom\u00e9dicas, Universidade do Algarve, 8005-139 Faro, Portugal"},{"name":"Programa de Doutoramento em Ci\u00eancias Biom\u00e9dicas, Faculdade de Medicina e Ci\u00eancias Biom\u00e9dicas, Universidade do Algarve, 8005-139 Faro, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patr\u00edcia","family":"Lima","sequence":"additional","affiliation":[{"name":"Algarve Biomedical Center\u2013Research Institute, 8005-139 Faro, Portugal"},{"name":"Faculdade de Medicina e Ci\u00eancias Biom\u00e9dicas, Universidade do Algarve, 8005-139 Faro, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"Algarve Biomedical Center\u2013Research Institute, 8005-139 Faro, Portugal"},{"name":"Faculdade de Medicina e Ci\u00eancias Biom\u00e9dicas, Universidade do Algarve, 8005-139 Faro, Portugal"},{"name":"Programa de Doutoramento em Ci\u00eancias Biom\u00e9dicas, Faculdade de Medicina e Ci\u00eancias Biom\u00e9dicas, Universidade do Algarve, 8005-139 Faro, Portugal"},{"name":"Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos A.","family":"Matos","sequence":"additional","affiliation":[{"name":"Algarve Biomedical Center\u2013Research Institute, 8005-139 Faro, Portugal"},{"name":"Faculdade de Medicina e Ci\u00eancias Biom\u00e9dicas, Universidade do Algarve, 8005-139 Faro, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8312-5292","authenticated-orcid":false,"given":"Cl\u00e9vio","family":"N\u00f3brega","sequence":"additional","affiliation":[{"name":"Algarve Biomedical Center\u2013Research Institute, 8005-139 Faro, Portugal"},{"name":"Faculdade de Medicina e Ci\u00eancias Biom\u00e9dicas, Universidade do Algarve, 8005-139 Faro, Portugal"},{"name":"Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0022-510X(89)90159-7","article-title":"Dominantly inherited olivopontocerebellar atrophy from eastern Cuba: Clinical, neuropathological, and biochemical findings","volume":"93","author":"Orozco","year":"1989","journal-title":"J. Neurol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1093\/brain\/94.2.359","article-title":"A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families)","volume":"94","author":"Wadia","year":"1971","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/ng1196-285","article-title":"Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG\/glutamine repeats","volume":"14","author":"Imbert","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/ng1196-277","article-title":"Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT","volume":"14","author":"Sanpei","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1212\/WNL.55.4.569","article-title":"Late-onset SCA2: 33 CAG repeats are sufficient to cause disease","volume":"55","author":"Fernandez","year":"2000","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-012-1000-x","article-title":"Brain pathology of spinocerebellar ataxias","volume":"124","author":"Seidel","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Afonso-Reis, R., Afonso, I., and N\u00f3brega, C. (2021). Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias-PubMed. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084249"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1385\/JMN:15:3:231","article-title":"The Ortholog of Human Ataxin-2 is Essential for Early Embryonic Patterning in C. elegans","volume":"15","author":"Kiehl","year":"2000","journal-title":"J. Mol. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1091\/mbc.e06-12-1120","article-title":"Ataxin-2 Interacts with the DEAD\/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules","volume":"18","author":"Nonhoff","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3648","DOI":"10.1038\/s41467-018-06041-3","article-title":"Staufen1 links RNA stress granules and autophagy in a model of neurodegeneration","volume":"9","author":"Paul","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jmb.2004.11.024","article-title":"An Integrative Approach to Gain Insights into the Cellular Function of Human Ataxin-2","volume":"346","author":"Ralser","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1093\/hmg\/9.9.1303","article-title":"A novel protein with RNA-binding motifs interacts with ataxin-2","volume":"9","author":"Shibata","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15810","DOI":"10.1074\/jbc.RA120.013835","article-title":"Direct evidence that Ataxin-2 is a translational activator mediating cytoplasmic polyadenylation","volume":"295","author":"Inagaki","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1093\/brain\/awv298","article-title":"Re-establishing ataxin-2 downregulates translation of mutant ataxin-3 and alleviates Machado\u2013Joseph disease","volume":"138","author":"Albuquerque","year":"2015","journal-title":"Brain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1093\/hmg\/ddn035","article-title":"Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice","volume":"17","author":"Brodesser","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dansithong, W., Paul, S., Figueroa, K.P., Rinehart, M.D., Wiest, S., Pflieger, L., Scoles, D.R., and Pulst, S.M. (2015). Ataxin-2 Regulates RGS8 Translation in a New BAC-SCA2 Transgenic Mouse Model. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005182"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9148","DOI":"10.1523\/JNEUROSCI.0660-09.2009","article-title":"Deranged Calcium Signaling and Neurodegeneration in Spinocerebellar Ataxia Type 2","volume":"29","author":"Liu","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1016\/j.cellsig.2008.05.018","article-title":"Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking","volume":"20","author":"Nonis","year":"2008","journal-title":"Cell. Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1093\/hmg\/ddi321","article-title":"Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways","volume":"14","author":"Ralser","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"N\u00f3brega, C., and de Almeida, L.P. (2018). Spinocerebellar Ataxia Type 2. Polyglutamine Disorders, Springer International Publishing.","DOI":"10.1007\/978-3-319-71779-1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/79162","article-title":"Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human","volume":"26","author":"Huynh","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"483","DOI":"10.11613\/BM.2019.030501","article-title":"Hallmarks of senescence and aging","volume":"29","author":"Dodig","year":"2019","journal-title":"Biochem. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.cell.2005.01.027","article-title":"Understanding the Odd Science of Aging","volume":"120","author":"Kirkwood","year":"2005","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The Hallmarks of Aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.cmet.2018.05.011","article-title":"Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States","volume":"27","author":"Mattson","year":"2018","journal-title":"Cell Metab."},{"key":"ref_27","first-page":"572","article-title":"Motor Dysfunctions and Neuropathology in Mouse Models of Spinocerebellar Ataxia Type 2: A Comprehensive Review","volume":"10","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/0197-4580(90)90024-T","article-title":"Cortical senile plaques in coronary artery disease, aging and Alzheimer\u2019s disease","volume":"11","author":"Sparks","year":"1990","journal-title":"Neurobiol. Aging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1148\/radiology.166.3.3277247","article-title":"Imaging of the aging brain. Part I. Normal findings","volume":"166","author":"Drayer","year":"1988","journal-title":"Radiology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1212\/WNL.49.3.786","article-title":"Medial temporal atrophy on MRI in normal aging and very mild Alzheimer\u2019s disease","volume":"49","author":"Jack","year":"1997","journal-title":"Neurology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1093\/brain\/awu174","article-title":"Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes","volume":"137","author":"Durr","year":"2014","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/s41419-021-04404-1","article-title":"Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy","volume":"12","author":"Marcelo","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3233\/JHD-200395","article-title":"Biological Aging and the Cellular Pathogenesis of Huntington\u2019s Disease","volume":"9","author":"Machiela","year":"2020","journal-title":"J. Huntington\u2019s Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.tins.2009.08.002","article-title":"Molecular dissection of reactive astrogliosis and glial scar formation","volume":"32","author":"Sofroniew","year":"2009","journal-title":"Trends Neurosci."},{"key":"ref_35","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\u2013Joseph disease","volume":"136","author":"Onofre","year":"2013","journal-title":"Brain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1007\/s00401-019-02019-7","article-title":"Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia","volume":"138","author":"Marcelo","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_37","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\u2013Joseph disease models","volume":"28","author":"Marcelo","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1111\/j.1365-2443.2011.01505.x","article-title":"Aging causes distinct characteristics of polyglutamine amyloids in vivo","volume":"16","author":"Tonoki","year":"2011","journal-title":"Genes Cells"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e43059","DOI":"10.7554\/eLife.43059","article-title":"Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans","volume":"8","author":"Huang","year":"2019","journal-title":"eLife"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3389\/fnagi.2017.00138","article-title":"Age-Dependent Protein Aggregation Initiates Amyloid-\u03b2 Aggregation","volume":"9","author":"Groh","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"a020628","DOI":"10.1101\/cshperspect.a020628","article-title":"Astrocytes in neurodegenerative disease","volume":"7","author":"Phatnani","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zahn, J.M., Poosala, S., Owen, A.B., Ingram, D.K., Lustig, A., Carter, A., Weeraratna, A.T., Taub, D.D., Gorospe, M., and Mazan-Mamczarz, K. (2007). AGEMAP: A Gene Expression Database for Aging in Mice. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030201"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/s004010050989","article-title":"Spinocerebellar ataxia 2 (SCA2): Morphometric analyses in 11 autopsies","volume":"97","author":"Estrada","year":"1999","journal-title":"Acta Neuropathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/ana.20054","article-title":"Reduced striatal [123I]FP-CIT binding in SCA2 patients without parkinsonism","volume":"55","author":"Varrone","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1093\/brain\/awf060","article-title":"Neuronal intranuclear inclusions in SCA2: A genetic, morphological and immunohistochemical study of two cases","volume":"125","author":"Pang","year":"2002","journal-title":"Brain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s12311-012-0432-0","article-title":"Overexpression of Mutant Ataxin-3 in Mouse Cerebellum Induces Ataxia and Cerebellar Neuropathology","volume":"12","author":"Onofre","year":"2013","journal-title":"Cerebellum"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"N\u00f3brega, C., Nascimento-Ferreira, I., Onofre, I., Albuquerque, D., D\u00e9glon, N., and de Almeida, L.P. (2014). RNA Interference Mitigates Motor and Neuropathological Deficits in a Cerebellar Mouse Model of Machado-Joseph Disease. 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