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While progress has been made in understanding molecular pathways involved in suicide, much more work is needed to identify clinically useful biomarkers of suicidality. Disturbed cellular proteostasis and aggregation of specific misfolded proteins are established pathological factors of neurodegenerative diseases. Increasing evidence also suggests that such aggregates often occur in patients with chronic mental illnesses. Recently, genes related to disturbed proteostasis showed differential methylation in individuals who died by suicide compared to controls. These include five genes encoding proteins that aggregate in neurodegenerative and\/or mental illness: CRMP1 (also called DPYSL1), DISC1, MAPT (encoding the Tau protein), PRKN (also called PARK2, encoding Parkin), and SOD1. Given the possibility that altered methylation in these genes could affect expression of the proteins they encode, we aimed to review evidence for whether disturbed proteostasis may be a point of overlap between suicidality, neurodegenerative disease, and\/or mental illnesses. Epigenetic changes in most of these genes also occur in other neurological disorders. Autophagy, and, to a lesser extent, the ubiquitin\u2013proteasome system, are emerging as potentially impaired in individuals with suicidal tendencies and individuals who died by suicide. Based on this accumulated data, we hypothesise that disturbed proteostasis is likely to be a pathological component of suicidality. It is also plausible that this may lead to the accumulation of aggregated proteins in a similar manner to, and potentially overlapping with, those seen in major mental illnesses. If true, this would have consequences for potential identification of biomarkers for suicidality and should be a priority for future research in the field.<\/jats:p>","DOI":"10.3390\/biom16050733","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T10:07:47Z","timestamp":1779444467000},"page":"733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Evidence Implies Disturbed Proteostasis and Potentially Protein Aggregation in Suicidality"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-832X","authenticated-orcid":false,"given":"Julija","family":"\u0160mon","sequence":"first","affiliation":[{"name":"Institute of Biochemistry & Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Jukovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Biotechnology & Drug Development, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matea","family":"Kr\u0161anac","sequence":"additional","affiliation":[{"name":"Faculty of Biotechnology & Drug Development, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7745-2337","authenticated-orcid":false,"given":"Bobana","family":"Samard\u017eija","sequence":"additional","affiliation":[{"name":"Faculty of Biotechnology & Drug Development, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1182-5417","authenticated-orcid":false,"given":"Alja","family":"Videti\u010d Paska","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry & Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9793-8200","authenticated-orcid":false,"given":"Eva","family":"\u017derovnik","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular and Structural Biology, Jo\u017eef Stefan Institute, 1000 Ljubljana, Slovenia"},{"name":"Jo\u017eef Stefan\u2019s International Postgraduate School, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1051-959X","authenticated-orcid":false,"given":"Katarina","family":"Kouter","sequence":"additional","affiliation":[{"name":"Institute of Microbiology & Immunology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5581-8828","authenticated-orcid":false,"given":"Nicholas J.","family":"Bradshaw","sequence":"additional","affiliation":[{"name":"Faculty of Biotechnology & Drug Development, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,16]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021). 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