Ali Mohammad, Wollenhaupt-Aguiar Bianca, Wang Yifan, Abu-Hijleh Fahed, Rigg Nicolette, de Azevedo Cardoso Taiane, Ahmed Imran, Gopalakrishnan Ridhi, Jansen Karen, de Mattos Souza Luciano Dias, Azevedo da Silva Ricardo, Mondin Thaise Campos, Kapczinski Flavio, Moreira Fernanda Pedrotti, Lofts Andrew, Gwynne William D, Hoare Todd, Mishra Ram, Frey Benicio N
MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, Ontario, Canada.
Centre for Clinical Neurosciences, McMaster University, Hamilton, Ontario, Canada.
Int J Neuropsychopharmacol. 2025 Feb 4;28(2). doi: 10.1093/ijnp/pyaf004.
Bipolar disorder (BD) has been associated with impaired cellular resilience. Recent studies have shown abnormalities in the unfolded protein response (UPR) in BD. The UPR is the cellular response to endoplasmic reticulum (ER) stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a trophic factor, decreases ER stress by modulating the UPR. The objective of this study is to investigate the MANF-ER stress pathway in BD and major depressive disorder (MDD) compared to healthy controls (HC).
MANF protein concentration and MANF and GRP78 gene expression were assessed in peripheral blood from individuals with BD, MDD, and HC (protein: 40 BD, 55 MDD, 55 HC; gene expression: 52 BD, 61 MDD, 69 HC). MANF protein and gene expression along with GRP78 gene expression were also analyzed in postmortem brain tissue (20 BD, 20 MDD, 19 HC). MANF protein was quantified using an ELISA assay while quantitative polymerase chain reaction was used for MANF and GRP78 gene expression.
Peripheral MANF protein levels were reduced in individuals with BD in a depressive state compared to controls (P = .031) and euthymic BD participants (P = .013). No significant differences in MANF or GRP78 gene expression were observed in BD irrespective of mood state, or MDD compared to HC (all P > .05). No differences were observed regarding MANF/GRP78 protein or gene expression levels in postmortem tissue (P > .05).
Individuals with BD who were in an acute depressive phase were found to have reduced peripheral MANF levels potentially signifying abnormal UPR and supporting the notion that BD is associated with increased ER stress.
双相情感障碍（BD）与细胞弹性受损有关。最近的研究表明BD患者的未折叠蛋白反应（UPR）存在异常。UPR是细胞对内质网（ER）应激的反应。中脑星形胶质细胞衍生的神经营养因子（MANF）是一种营养因子，可通过调节UPR来减轻ER应激。本研究的目的是调查与健康对照（HC）相比，BD和重度抑郁症（MDD）中的MANF-ER应激途径。
评估了BD、MDD患者及HC外周血中MANF蛋白浓度以及MANF和GRP78基因表达（蛋白：40例BD、55例MDD、55例HC；基因表达：52例BD、61例MDD、69例HC）。还分析了死后脑组织中MANF蛋白和基因表达以及GRP78基因表达（20例BD、20例MDD、19例HC）。使用酶联免疫吸附测定法对MANF蛋白进行定量，而定量聚合酶链反应用于检测MANF和GRP78基因表达。
与对照组（P = 0.031）和心境正常的BD参与者（P = 0.013）相比，处于抑郁状态的BD患者外周MANF蛋白水平降低。无论情绪状态如何，BD患者与HC相比，MANF或GRP78基因表达均无显著差异（所有P>0.05）。死后组织中MANF/GRP78蛋白或基因表达水平无差异（P>0.05）。
发现处于急性抑郁期的BD患者外周MANF水平降低，这可能表明UPR异常，并支持BD与ER应激增加有关的观点。
