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We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with \u03b1\u2010synuclein pathology in human post\u2010mortem brain tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analysed brain tissue from 45 subjects\u201414 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response\u2010related proteins (Grp78, eIF2\u03b1) and endoplasmic reticulum stress\u2010regulating neurotrophic factors (MANF, CDNF).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We showed that regional levels of two endoplasmic reticulum\u2010localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating \u03b1\u2010synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2\u03b1 was upregulated in the striatum of Lewy body disease patients and correlated with increased \u03b1\u2010synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble \u03b1\u2010synuclein levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data suggest a strong but regionally specific change in Grp78 and eIF2\u03b1 levels, which positively correlates with soluble \u03b1\u2010synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble \u03b1\u2010synuclein concentration and disease progression.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12999","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T09:26:31Z","timestamp":1721640391000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Unfolded protein response markers Grp78 and eIF2alpha are upregulated with increasing alpha\u2010synuclein levels in Lewy body disease"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9856-0126","authenticated-orcid":false,"given":"Dominik","family":"Hrabos","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neuroscience University of Oxford  Oxford UK"},{"name":"Department of Clinical and Molecular Pathology Palacky University Olomouc and University Hospital Olomouc  Olomouc Czech\u00a0Republic"},{"name":"Department of Neurology Palacky University Olomouc and University Hospital Olomouc  Olomouc Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Poggiolini","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neuroscience University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Civitelli","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neuroscience University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Galli","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Helsinki Institute of Life Science University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Esapa","sequence":"additional","affiliation":[{"name":"Mammalian Genetics Unit MRC Harwell Institute, Harwell Science and Innovation Campus  Didcot UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart","family":"Saarma","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Helsinki Institute of Life Science University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"Lindholm","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Helsinki Institute of Life Science University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3392-8564","authenticated-orcid":false,"given":"Laura","family":"Parkkinen","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neuroscience 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