15-deoxy-delta(12-14)-prostaglandin-j2 and Amyotrophic-Lateral-Sclerosis

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-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is non-enzymatically produced from PGD(2) and plays roles in inflammation and oxidative stress responses. Indeed, 15d-PGJ(2) is up-regulated in the spinal motor neurons in amyotrophic lateral sclerosis. In this study, biochemical and immunocytochemical analyses showed that 15d-PGJ(2) 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-PGJ(2) is likely to influence these phenomena. These findings suggest that 15d-PGJ(2) is an endogenous modifier of TDP-43 protein in TDP-43 proteinopathy.

Topics: Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Cell Line; Cyclopentanes; Cytoplasm; DNA-Binding Proteins; Female; Gene Expression Regulation; Humans; Immunologic Factors; Male; Middle Aged; Neuroblastoma; Prostaglandin D2; Spinal Cord; Subcellular Fractions