{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:20:14Z","timestamp":1782433214059,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Association for Cancer Research","award":["22818"],"award-info":[{"award-number":["22818"]}]},{"name":"Italian Association for Cancer Research","award":["2019-1609"],"award-info":[{"award-number":["2019-1609"]}]},{"name":"Italian Association for Cancer Research","award":["RCR-2022-23682288"],"award-info":[{"award-number":["RCR-2022-23682288"]}]},{"name":"Cariplo Foundation","award":["22818"],"award-info":[{"award-number":["22818"]}]},{"name":"Cariplo Foundation","award":["2019-1609"],"award-info":[{"award-number":["2019-1609"]}]},{"name":"Cariplo Foundation","award":["RCR-2022-23682288"],"award-info":[{"award-number":["RCR-2022-23682288"]}]},{"name":"Ricerca Corrente Retie Cardiologica IRCCS 2022","award":["22818"],"award-info":[{"award-number":["22818"]}]},{"name":"Ricerca Corrente Retie Cardiologica IRCCS 2022","award":["2019-1609"],"award-info":[{"award-number":["2019-1609"]}]},{"name":"Ricerca Corrente Retie Cardiologica IRCCS 2022","award":["RCR-2022-23682288"],"award-info":[{"award-number":["RCR-2022-23682288"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is caused by the production of mutant Huntingtin (mHTT), characterized by long polyglutamine repeats with toxic effects. There are currently no clinically validated therapeutic agents that slow or halt HD progression, resulting in a significant clinical unmet need. The striatum-derived STHdh cell line, generated from mHTT knock-in mouse embryos (STHdhQ111\/Q111), represents a useful model to study mechanisms behind pathogenesis of HD and to investigate potential new therapeutic targets. Indeed, these cells show susceptibility to nucleolar stress, activated DNA damage response and apoptotic signals, and elevated levels of H3K9me3 that all together concur in the progressive HD pathogenesis. We have previously shown that the adeno-associated viral vector-mediated delivery of the longevity-associated variant (LAV) of BPIFB4 prevents HD progression in a mouse model of HD. Here, we show that LAV-BPIFB4 stably infected in STHdhQ111\/Q111 cells reduces (i) nucleolar stress and DNA damage through the improvement of DNA repair machinery, (ii) apoptosis, through the inhibition of the caspase 3 death signaling, and (iii) the levels of H3K9me3, by accelerating the histone clearance, via the ubiquitin\u2013proteasome pathway. These findings pave the way to propose LAV-BPIFB4 as a promising target for innovative therapeutic strategies in HD.<\/jats:p>","DOI":"10.3390\/ijms232315313","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T02:13:12Z","timestamp":1670206392000},"page":"15313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Longevity-Associated Variant of BPIFB4 Confers Neuroprotection in the STHdh Cell Model of Huntington Disease"],"prefix":"10.3390","volume":"23","author":[{"given":"Monica","family":"Cattaneo","sequence":"first","affiliation":[{"name":"Cardiovascular Department, IRCCS MultiMedica, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6562-5640","authenticated-orcid":false,"given":"Anna","family":"Maciag","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, IRCCS MultiMedica, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5558-7601","authenticated-orcid":false,"given":"Maria Serena","family":"Milella","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, IRCCS MultiMedica, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-4583","authenticated-orcid":false,"given":"Elena","family":"Ciaglia","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-0861","authenticated-orcid":false,"given":"Antonino","family":"Bruno","sequence":"additional","affiliation":[{"name":"Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry and Immunology, IRCCS MultiMedica, 20138 Milan, Italy"},{"name":"Laboratory of Immunology and General Pathology, Department of Biotechnologies and Life Sciences (DBSV), University of Insubria, 20138 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0347-1460","authenticated-orcid":false,"given":"Annibale Alessandro","family":"Puca","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, IRCCS MultiMedica, 20138 Milan, Italy"},{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"The Huntington\u2019s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. Cell, 72, 971\u2013983.","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","article-title":"Neuropathological classification of Huntington\u2019s disease","volume":"44","author":"Vonsattel","year":"1985","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1093\/hmg\/ddn175","article-title":"Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington\u2019s disease","volume":"17","author":"Wang","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1111\/j.1471-4159.2005.03605.x","article-title":"Wild-type huntingtin protects neurons from excitotoxicity","volume":"96","author":"Leavitt","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9455","DOI":"10.1523\/JNEUROSCI.4699-13.2014","article-title":"Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits","volume":"34","author":"McKinstry","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.nbd.2017.12.015","article-title":"Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum","volume":"111","author":"Dragatsis","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1523\/JNEUROSCI.2443-18.2018","article-title":"Loss-of-Huntingtin in Medial and Lateral Ganglionic Lineages Differentially Disrupts Regional Interneuron and Projection Neuron Subtypes and Promotes Huntington\u2019s Disease-Associated Behavioral, Cellular, and Pathological Hallmarks","volume":"39","author":"Mehler","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"799","DOI":"10.4161\/rna.19718","article-title":"RNA-binding protein nucleolin in disease","volume":"9","author":"Abdelmohsen","year":"2012","journal-title":"RNA Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13428","DOI":"10.1073\/pnas.1204089109","article-title":"CAG expansion induces nucleolar stress in polyglutamine diseases","volume":"109","author":"Tsoi","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1093\/hmg\/ddm064","article-title":"Modulation of nucleosome dynamics in Huntington\u2019s disease","volume":"16","author":"Stack","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19176","DOI":"10.1073\/pnas.0606373103","article-title":"ESET\/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington\u2019s disease","volume":"103","author":"Ryu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1080\/14756366.2021.1900160","article-title":"Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington\u2019s disease mouse model","volume":"36","author":"Hwang","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1093\/hmg\/ddg242","article-title":"DNA damage induced by polyglutamine-expanded proteins","volume":"12","author":"Giuliano","year":"2003","journal-title":"Hum. Mol Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/jnr.21881","article-title":"DNA breakage and induction of DNA damage response proteins precede the appearance of visible mutant huntingtin aggregates","volume":"87","author":"Illuzzi","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1083\/jcb.200905138","article-title":"Mutant huntingtin impairs Ku70-mediated DNA repair","volume":"189","author":"Enokido","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Villa, F., Carrizzo, A., Ferrario, A., Maciag, A., Cattaneo, M., Spinelli, C.C., Montella, F., Damato, A., Ciaglia, E., and Puca, A.A. (2018). A Model of Evolutionary Selection: The Cardiovascular Protective Function of the Longevity Associated Variant of BPIFB4. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103229"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1161\/CIRCRESAHA.117.305875","article-title":"Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis","volume":"117","author":"Villa","year":"2015","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12979-015-0054-8","article-title":"Serum BPIFB4 levels classify health status in long-living individuals","volume":"12","author":"Villa","year":"2015","journal-title":"Immun. Ageing"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1093\/eurheartj\/ehz459","article-title":"Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism","volume":"41","author":"Puca","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1002\/ejhf.1840","article-title":"Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the SDF-1\/CXCR4 signalling pathway","volume":"22","author":"Dang","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6555","DOI":"10.18632\/aging.102209","article-title":"LAV-BPIFB4 associates with reduced frailty in humans and its transfer prevents frailty progression in old mice","volume":"11","author":"Malavolta","year":"2019","journal-title":"Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s41419-020-02754-w","article-title":"The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum-microglia crosstalk preventing disease progression in a mouse model of Huntington\u2019s disease","volume":"11","author":"Ciaglia","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41419-022-04535-z","article-title":"Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline","volume":"13","author":"Ciaglia","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1093\/cvr\/cvx072","article-title":"LAV-BPIFB4 isoform modulates eNOS signalling through Ca2+\/PKC-alpha-dependent mechanism","volume":"113","author":"Spinelli","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1093\/hmg\/9.19.2799","article-title":"Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells","volume":"9","author":"Trettel","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.1096\/fj.14-254680","article-title":"Connecting the nucleolus to the cell cycle and human disease","volume":"28","author":"Tsai","year":"2014","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11390","DOI":"10.1038\/ncomms11390","article-title":"Involvement of human ribosomal proteins in nucleolar structure and p53-dependent nucleolar stress","volume":"7","author":"Nicolas","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.bbadis.2013.09.016","article-title":"Stressing on the nucleolus in cardiovascular disease","volume":"1842","author":"Hariharan","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1016\/j.cell.2015.05.032","article-title":"Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes","volume":"161","author":"Madabhushi","year":"2015","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"522","DOI":"10.7150\/ijms.5325","article-title":"IGF-1 acts as controlling switch for long-term proliferation and maintenance of EGF\/FGF-responsive striatal neural stem cells","volume":"10","author":"Supeno","year":"2013","journal-title":"Int. J. Med. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kobayashi, J., Fujimoto, H., Sato, J., Hayashi, I., Burma, S., Matsuura, S., Chen, D.J., and Komatsu, K. (2012). Nucleolin participates in DNA double-strand break-induced damage response through MDC1-dependent pathway. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049245"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16874","DOI":"10.1073\/pnas.1306160110","article-title":"Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair","volume":"110","author":"Goldstein","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3389\/fnagi.2017.00383","article-title":"Hippocampal Transcriptomic Profiles: Subfield Vulnerability to Age and Cognitive Impairment","volume":"9","author":"Ianov","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41392-022-01078-9","article-title":"The role of histone modifications: From neurodevelopment to neurodiseases","volume":"7","author":"Park","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13073-020-00749-y","article-title":"Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford progeria syndrome","volume":"12","author":"Bormann","year":"2020","journal-title":"Genome Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.1365-2443.2008.01252.x","article-title":"Genome-wide histone methylation profile for heart failure","volume":"14","author":"Kaneda","year":"2009","journal-title":"Genes Cells"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20164","DOI":"10.1073\/pnas.1315155110","article-title":"Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy","volume":"110","author":"Papait","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e13153","DOI":"10.1111\/acel.13153","article-title":"Epigenome signatures landscaped by histone H3K9me3 are associated with the synaptic dysfunction in Alzheimer\u2019s disease","volume":"19","author":"Lee","year":"2020","journal-title":"Aging Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/hmg\/ddx432","article-title":"Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington\u2019s disease","volume":"27","author":"Song","year":"2018","journal-title":"Hum. Mol. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/15313\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:34:01Z","timestamp":1760146441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/15313"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,5]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232315313"],"URL":"https:\/\/doi.org\/10.3390\/ijms232315313","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,5]]}}}