Alteration of biochemical and pathological properties of TDP-43 protein by a lipid mediator, 15-deoxy-Δ12,14-prostaglandin J2

TDP-43 proteinopathy (amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions) is a newly categorized group of neurodegenerative disorders characterized by abnormal accumulation and mislocalization of nuclear TDP-43 protein in the neuronal cytoplasm. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is non-enzymatically produced from PGD2 and plays roles in inflammation and oxidative stress responses. Indeed, 15d-PGJ2 is up-regulated in the spinal motor neurons in amyotrophic lateral sclerosis. In this study, biochemical and immunocytochemical analyses showed that 15d-PGJ2 affects the proteolysis, solubility, and subcellular localization of TDP-43, similar to alterations found in TDP-43 proteinopathy. Further studies revealed that a cyclopentenone ring containing an electrophilic carbon of 15d-PGJ2 is likely to influence these phenomena. These findings suggest that 15d-PGJ2 is an endogenous modifier of TDP-43 protein in TDP-43 proteinopathy.