Investigation of the Mesencephalic Astrocyte Derived Neurotrophic Factor-Endoplasmic Reticulum Stress Pathway in Mood Disorders

Mohammad Ali; Bianca Wollenhaupt-Aguiar; Yifan Wang; Fahed Abu-Hijleh; Nicolette Rigg; Taiane de Azevedo Cardoso; Imran Ahmed; Ridhi Gopalakrishnan; Karen Jansen; Luciano Dias de Mattos Souza; Ricardo Azevedo da Silva; Thaise Campos Mondin; Flavio Kapczinski; Fernanda Pedrotti Moreira; Andrew Lofts; William D Gwynne; Todd Hoare; Ram Mishra; Benicio N Frey

doi:10.1093/ijnp/pyaf004

Investigation of the Mesencephalic Astrocyte Derived Neurotrophic Factor-Endoplasmic Reticulum Stress Pathway in Mood Disorders

Int J Neuropsychopharmacol. 2025 Jan 13:pyaf004. doi: 10.1093/ijnp/pyaf004. Online ahead of print.

Authors

Mohammad Ali^{1

2}, Bianca Wollenhaupt-Aguiar^{2

3}, Yifan Wang^{2

4}, Fahed Abu-Hijleh¹, Nicolette Rigg¹, Taiane de Azevedo Cardoso⁵, Imran Ahmed^{6

7

8}, Ridhi Gopalakrishnan², Karen Jansen⁹, Luciano Dias de Mattos Souza⁹, Ricardo Azevedo da Silva⁹, Thaise Campos Mondin¹⁰, Flavio Kapczinski^{11

12

13

14}, Fernanda Pedrotti Moreira⁹, Andrew Lofts¹⁵, William D Gwynne^{16

17}, Todd Hoare^{15

18}, Ram Mishra¹¹, Benicio N Frey^{2

11

3}

Affiliations

¹ MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, ON.
² Centre for Clinical Neurosciences, McMaster University, Hamilton, ON.
³ Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
⁴ University of Ottawa Medical School.
⁵ IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Australia.
⁶ Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON.
⁷ Michael G. Degroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario.
⁸ McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario.
⁹ Department of Health and Behavior, Catholic University of Pelotas, Pelotas, Brazil.
¹⁰ Department of Student Affairs, Federal University of Pelotas, Pelotas, RS, Brazil.
¹¹ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON.
¹² Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
¹³ Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁴ Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, Brazil.
¹⁵ School of Biomedical Engineering, McMaster University, 1280 Main Street, West Hamilton, ON, L8S 4L8, Canada.
¹⁶ Department of Surgery, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
¹⁷ Center for Discovery in Cancer Research (CDCR), McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
¹⁸ Department of Chemical Engineering, McMaster University, 1280 Main Street, West Hamilton, ON, L8S 4L8, Canada.

PMID: 39803900
DOI: 10.1093/ijnp/pyaf004

Abstract

Background: 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).

Methods: 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.

Results: Peripheral MANF protein levels were reduced in individuals with BD in a depressive state compared to controls (p=0.031) and euthymic BD participants (p=0.013). No significant differences in MANF or GRP78 gene expression were observed in BD irrespective of mood state, or MDD compared to HC (all p>0.05). No differences were observed regarding MANF/GRP78 protein or gene expression levels in postmortem tissue (p>0.05).

Conclusion: 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.

Keywords: Bipolar disorder; GRP78; MANF; MDD; UPR; endoplasmic reticulum (ER) stress; mood disorders.