Manf-neuroplastin pathway

The presentation of diabetes mellitus is a phenotype of Wolfram and Wolfram-like Syndrome. Diabetes mellitus is a group of disorders that is characterized by a decrease in pancreatic β-cell insulin secretion. The Urano Lab has shown that endoplasmic reticulum (ER) dysregulation is a prerequisite to β-cell loss and dysfunction in type 1 and type 2 diabetes, as well as in Wolfram Syndrome. Increased ER stress has been suggested to increase sterile inflammation in pancreatic islets. However, the mechanism by which ER stress could cause this sterile inflammation is still unknown and there is no current treatment for ER stress for diabetes. The Urano Lab is currently investigating the role of WFS1 and MANF in mediation of NPTN, resulting in decreased β-cell inflammation and prevention of β-cell dysfunction and death. 

Selected Associated Publications 

Abreu D, Asada R, Revilla JMP, Lavagnino Z, Kries K, Piston DW, Urano F. Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival. Lab Invest. 2020 Jun;100(6):849-862. doi: 10.1038/s41374-020-0408-5. Epub 2020 Feb 14. PMID: 32060407; PMCID: PMC7286786. 

Morikawa S, Blacher L, Onwumere C, Urano F. Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells. Front Endocrinol (Lausanne). 2022 Mar 25;13:849204. doi: 10.3389/fendo.2022.849204. PMID: 35399956; PMCID: PMC8990750. 

Mahadevan J, Morikawa S, Yagi T, Abreu D, Lu S, Kanekura K, Brown CM, Urano F. A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome. Lab Invest. 2020 Sep;100(9):1197-1207. doi: 10.1038/s41374-020-0436-1. Epub 2020 May 4. PMID: 32366942; PMCID: PMC7438202. 

Yagi T, Asada R, Kanekura K, Eesmaa A, Lindahl M, Saarma M, Urano F. Neuroplastin Modulates Anti-inflammatory Effects of MANF. iScience. 2020 Nov 17;23(12):101810. doi: 10.1016/j.isci.2020.101810. PMID: 33299977; PMCID: PMC7702011.