Alteration of biochemical and pathological properties of TDP-43 protein by a lipid mediator, 15-deoxy-Delta(12,14)-prostaglandin J(2).
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.
Zhang
Hai-Xin
HX
Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
Tanji
Kunikazu
K
Yoshida
Hidemi
H
Hayakari
Makoto
M
Shibata
Takahiro
T
Mori
Fumiaki
F
Uchida
Koji
K
Wakabayashi
Koichi
K
D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009447:Neuroblastoma; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D003517:Cyclopentanes; D004268:DNA-Binding Proteins; D007155:Immunologic Factors; C013905:cyclopentenone; D015230:Prostaglandin D2