{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:45Z","timestamp":1787028465234,"version":"build-2736575974"},"reference-count":51,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,12,4]],"date-time":"2021-12-04T00:00:00Z","timestamp":1638576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS110694"],"award-info":[{"award-number":["R01NS110694"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biomedical Research Awards for Interdisciplinary New Science (BRAINS) University of Minnesota","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington\u2019s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute reduction in cell lines and mice decreased PSD-95 expression. Furthermore, Hsf1(+\/\u2212) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.<\/jats:p>","DOI":"10.3390\/ijms222313113","type":"journal-article","created":{"date-parts":[[2021,12,5]],"date-time":"2021-12-05T21:01:45Z","timestamp":1638738105000},"page":"13113","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Heat Shock Factor 1 Directly Regulates Postsynaptic Scaffolding PSD-95 in Aging and Huntington\u2019s Disease and Influences Striatal Synaptic Density"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4839-7783","authenticated-orcid":false,"given":"Nicole","family":"Zarate","sequence":"first","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor A.","family":"Intihar","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahyun","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Sawyer","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6490-2212","authenticated-orcid":false,"given":"Wei","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Syed","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1136-5462","authenticated-orcid":false,"given":"Rocio","family":"Gomez-Pastor","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1126\/science.290.5495.1364","article-title":"PSD-95 involvement in maturation of excitatory synapses","volume":"290","author":"Schnell","year":"2000","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19535","DOI":"10.1073\/pnas.0608492103","article-title":"Synapse-specific regulation of AMPA receptor function by PSD-95","volume":"103","author":"Lin","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.pbb.2015.05.013","article-title":"Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice","volume":"135","author":"Li","year":"2015","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.expneurol.2012.06.033","article-title":"Age-dependent decline of motor neocortex but not hippocampal performance in heterozygous BDNF mice correlates with a decrease of cortical PSD-95 but an increase of hippocampal TrkB levels","volume":"237","author":"Giralt","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1523\/JNEUROSCI.0151-13.2014","article-title":"Hsp90 chaperone inhibitor 17-AAG Attenuates A\u03b2-induced synaptic toxicity and memory impairment","volume":"34","author":"Chen","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1093\/hmg\/ddl013","article-title":"Regional and cellular gene expression changes in human Huntington\u2019s disease brain","volume":"15","author":"Hodges","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"29603","DOI":"10.1074\/jbc.M115.668889","article-title":"Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR)-dependent Transcription of PSD-95 and \u03b1-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons","volume":"290","author":"Qin","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/nn1342","article-title":"Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos","volume":"7","author":"Bao","year":"2004","journal-title":"Nat. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nn.3026","article-title":"PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2","volume":"15","author":"Zheng","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/dvdy.1223","article-title":"Ikaros expression as a marker for lymphoid progenitors during zebrafish development","volume":"222","author":"Willett","year":"2001","journal-title":"Dev. Dyn."},{"key":"ref_11","first-page":"4","article-title":"Regulation of heat shock transcription factors and their roles in physiology and disease","volume":"19","author":"Burchfiel","year":"2017","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"69","DOI":"10.4103\/1673-5374.264459","article-title":"Excitatory synapse impairment and mitochondrial dysfunction in Huntington\u2019s disease: Heat shock factor 1 (HSF1) converging mechanisms","volume":"15","author":"Zarate","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1007\/s12192-016-0709-1","article-title":"The central role of heat shock factor 1 in synaptic fidelity and memory consolidation","volume":"21","author":"Hooper","year":"2016","journal-title":"Cell Stress Chaperones"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7974","DOI":"10.1523\/JNEUROSCI.0006-07.2007","article-title":"Demyelination, astrogliosis, and accumulation of ubiquitinated proteins, hallmarks of CNS disease in hsf1-deficient mice","volume":"27","author":"Homma","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3389\/fnins.2017.00248","article-title":"The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease","volume":"11","author":"Gorenberg","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1046\/j.1471-4159.2000.740641.x","article-title":"Localization of the Heat-Shock Protein Hsp70 to the Synapse Following Hyperthermic Stress in the Brain","volume":"74","author":"Bechtold","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1073\/pnas.1016424108","article-title":"Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1","volume":"108","author":"Uchida","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.bbr.2008.05.024","article-title":"Basal behavioral characterization of hsf1 deficient mice and its cellular and behavioral abnormalities underlying chronic unpredictable stressors","volume":"193","author":"Zhu","year":"2008","journal-title":"Behav. Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14405","DOI":"10.1038\/ncomms14405","article-title":"Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington\u2019s disease","volume":"8","author":"Burchfiel","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/acn3.211","article-title":"Low neural exosomal levels of cellular survival factors in Alzheimer\u2019s disease","volume":"2","author":"Goetzl","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chafekar, S.M., and Duennwald, M.L. (2012). Impaired Heat Shock Response in Cells Expressing Full-Length Polyglutamine-Expanded Huntingtin. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037929"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1093\/hmg\/ddt667","article-title":"Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington\u2019s disease","volume":"23","author":"Maheshwari","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1093\/hmg\/ddv445","article-title":"NEDD4-mediated HSF1 degradation underlies \u03b1-synucleinopathy","volume":"25","author":"Kim","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes","volume":"72","author":"MacDonald","year":"1993","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Peng, Q., Wu, B., Jiang, M., Jin, J., Hou, Z., Zheng, J., Zhang, J., and Duan, W. (2016). Characterization of Behavioral, Neuropathological, Brain Metabolic and Key Molecular Changes in zQ175 Knock-In Mouse Model of Huntington\u2019s Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0148839"},{"key":"ref_26","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_27","doi-asserted-by":"crossref","first-page":"10160","DOI":"10.1073\/pnas.1804641115","article-title":"Dedifferentiation of caudate functional connectivity and striatal dopamine transporter density predict memory change in normal aging","volume":"115","author":"Rieckmann","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8453","DOI":"10.1523\/JNEUROSCI.0769-18.2018","article-title":"Feedback-Based Learning in Aging: Contributions and Trajectories of Change in Striatal and Hippocampal Systems","volume":"38","author":"Lighthall","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/(SICI)1098-2396(199709)27:1<57::AID-SYN6>3.0.CO;2-C","article-title":"Age-related change in short-term synaptic plasticity intrinsic to excitatory striatal synapses","volume":"27","author":"Ou","year":"1997","journal-title":"Synapse"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Menalled, L.B., Kudwa, A.E., Miller, S., Fitzpatrick, J., Watson-Johnson, J., Keating, N., Ruiz, M., Mushlin, R., Alosio, W., and McConnell, K. (2012). Comprehensive Behavioral and Molecular Characterization of a New Knock-In Mouse Model of Huntington\u2019s Disease: zQ175. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049838"},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1002\/hbm.22296","article-title":"Functional magnetic resonance imaging of working memory in Huntington\u2019s disease: Cross-sectional data from the IMAGE-HD study","volume":"35","author":"Stout","year":"2014","journal-title":"Hum. Brain Mapp."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.31887\/DCNS.2013.15.1\/jhenley","article-title":"AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging","volume":"15","author":"Henley","year":"2013","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fnana.2015.00154","article-title":"Postsynaptic Density Protein 95 in the Striosome and Matrix Compartments of the Human Neostriatum","volume":"9","author":"Morigaki","year":"2015","journal-title":"Front. Neuroanat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1093\/gerona\/glz204","article-title":"Multifactorial Attenuation of the Murine Heat Shock Response With Age","volume":"75","author":"Jurivich","year":"2020","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.nbd.2007.11.006","article-title":"Gene\u2013environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington\u2019s disease transgenic mice","volume":"29","author":"Nithianantharajah","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4510","DOI":"10.1093\/hmg\/ddu166","article-title":"Progressive axonal transport and synaptic protein changes correlate with behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse model of Huntington\u2019s disease","volume":"23","author":"Smith","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","first-page":"938530","article-title":"Differential Changes in Postsynaptic Density Proteins in Postmortem Huntington\u2019s Disease and Parkinson\u2019s Disease Human Brains","volume":"2014","author":"Fourie","year":"2014","journal-title":"J. Neurodegener. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Carty, N., Berson, N., Tillack, K., Thiede, C., Scholz, D., Kottig, K., Sedaghat, Y., Gabrysiak, C., Yohrling, G., and Kammer, H.v.d. (2015). Characterization of HTT Inclusion Size, Location, and Timing in the zQ175 Mouse Model of Huntington\u2019s Disease: An In Vivo High-Content Imaging Study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123527"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.brainresbull.2008.08.015","article-title":"The Thalamostriatal Systems: Anatomical and Functional Organization in Normal and Parkinsonian States","volume":"78","author":"Smith","year":"2009","journal-title":"Brain Res. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1007\/s00429-013-0601-z","article-title":"Convergence of cortical and thalamic input to direct and indirect pathway medium spiny neurons in the striatum","volume":"219","author":"Bolam","year":"2014","journal-title":"Brain Struct. Funct."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"30459","DOI":"10.1074\/jbc.M114.591578","article-title":"Genomic heat shock element sequences drive cooperative human heat shock factor 1 DNA binding and selectivity","volume":"289","author":"Jaeger","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0002-9440(10)63436-0","article-title":"Synaptic changes in Alzheimer\u2019s disease: Increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence","volume":"165","author":"Gylys","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1101\/gad.1657108","article-title":"Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging","volume":"22","author":"Morimoto","year":"2008","journal-title":"Genes Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1111\/j.1476-5381.2011.01204.x","article-title":"Transcriptional activation of the anchoring protein SAP97 by heat shock factor (HSF)-1 stabilizes K v 1.5 channels in HL-1 cells","volume":"162","author":"Ting","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3233\/JHD-2012-120020","article-title":"Poly-glutamine expanded huntingtin dramatically alters the genome wide binding of HSF1","volume":"1","author":"Riva","year":"2012","journal-title":"J. Huntingtons. Dis."},{"key":"ref_47","unstructured":"Yu, D., Zarate, N., Cuccu, F., Yue, J.S., Brown, T.G., Tsai, A., Mansky, R., Jiang, K., Kim, H., and Nanclares, C. (2020). Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington\u2019s disease. bioRxiv."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.neuroscience.2012.05.043","article-title":"Dysregulation of synaptic proteins, dendritic spine abnormalities and pathological plasticity of synapses as experience-dependent mediators of cognitive and psychiatric symptoms in Huntington\u2019s disease","volume":"251","author":"Nithianantharajah","year":"2013","journal-title":"Neuroscience"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.tins.2010.08.002","article-title":"Early synaptic pathophysiology in neurodegeneration: Insights from Huntington\u2019s disease","volume":"33","author":"Milnerwood","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Heikkinen, T., Lehtim\u00e4ki, K., Vartiainen, N., Puoliv\u00e4li, J., Hendricks, S.J., Glaser, J.R., Bradaia, A., Wadel, K., Touller, C., and Kontkanen, O. (2012). Characterization of Neurophysiological and Behavioral Changes, MRI Brain Volumetry and 1H MRS in zQ175 Knock-In Mouse Model of Huntington\u2019s Disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050717"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/13113\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:39:41Z","timestamp":1760168381000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/13113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,4]]},"references-count":51,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222313113"],"URL":"https:\/\/doi.org\/10.3390\/ijms222313113","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202111.0082.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,4]]}}}