title: Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration.
abstract: In the majority of neurodegenerative storage disorders, neuronal death in the brain is followed by infiltration of phagocytic cells (e.g. activated microglia, astroglia and macrophages) for the efficient removal of cell corpses. However, it is increasingly evident that these phagocytes may also cause death of adjoining viable neurons contributing to rapid progression of neurodegeneration. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating, neurodegenerative, lysosomal storage disorder caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 catalyzes the cleavage of thioester linkages in S-acylated (palmitoylated) proteins and its deficiency leads to abnormal accumulation of thioesterified polypeptides (ceroid) in lysosomes causing INCL pathogenesis. PPT1-knockout (PPT1-KO) mice mimic the clinical and pathological features of human INCL including rapid neuronal death by apoptosis and phagocyte infiltration. We previously reported that in PPT1-KO mice, the neurons undergo endoplasmic reticulum stress activating unfolded protein response, which mediates caspase-12 activation and apoptosis. However, the molecular mechanism(s) by which the phagocytic cells are recruited in the PPT1-KO mouse brain remains poorly understood. We report here that increased production of lysophosphatidylcholine (LPC), catalyzed by the activation of cytosolic phospholipase A(2) (cPLA(2)) in the PPT1-KO mouse brain, is a 'lipid signal' for phagocyte recruitment. We also report that an age-dependent increase in LPC levels in the PPT1-KO mouse brain positively correlates with elevated expression of the genes characteristically associated with phagocytes. We propose that increased cPLA(2)-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology.
authors.affiliation: Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Developement, The National Institutes of Health, Bethesda, MD 20892-1830, USA.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lee
authors.forename: Sung-Jo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Moonsuk S
authors.initials: MS
authors.lastname: Choi
authors.forename: Pei-Chih
authors.initials: PC
authors.lastname: Tsai
authors.forename: Arjun
authors.initials: A
authors.lastname: Saha
authors.forename: Hui
authors.initials: H
authors.lastname: Wei
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Yi-Jin
authors.initials: YJ
authors.lastname: Xiao
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Alison
authors.initials: A
authors.lastname: Heffer
authors.forename: Anil B
authors.initials: AB
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002465:Cell Movement; D004789:Enzyme Activation; D037161:Galectins / Q000378:metabolism; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000502:physiology; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D010586:Phagocytes / Q000166:cytology / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D021241:Spectrometry, Mass, Electrospray Ionization; D013869:Thiolester Hydrolases / Q000235:genetics*; D013997:Time Factors
chemical_list: D037161:Galectins; D005904:Glial Fibrillary Acidic Protein; D008244:Lysophosphatidylcholines; D010741:Phospholipases A; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase