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.

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

“…Although, the involvement of CD4ϩ and CD8ϩ T cell recruitment in neuroinflammation has been previously reported in neurodegenerative diseases (Brisebois et al, 2006;Brochard et al, 2009), this is the first report showing that p25 overexpression may initiate the peripheral cell recruitment into the mice brain to exacerbate neuroinflammation. LPC has previously been shown to be a chemoattractant for T cells (Ousman and David, 2000;Zhang et al, 2007), therefore it is reasonable to believe that p25-mediated LPC production is responsible for this peripheral cell recruitment.…”

Endoplasmic-Reticulum Calcium Depletion and Disease

“…In Sandhoff disease, SERCA activity is inhibited by the accumulation of G M2 -ganglioside , which depends on an exposed sialic-acid residue on G M2 (Ginzburg et al 2008). The UPR is also activated by the accumulation of palmitoylated proteins in the infantile form of Batten disease, but ER Ca 2þ handling was not investigated (Zhang et al 2007). The decreased SERCA2 and IP 3 R1 expression in Niemann-Pick A disease did not activate a UPR (Ginzburg and Futerman 2005).…”

Metabolomics predicts stroke recurrence after transient ischemic attack

“…19 LysoPC(16:0) by itself increases on brain after stroke 20,21 where it mediates phagocyte recruiting 22 that can contribute to ischemic brain injury 23 and also produces neuroinflammatory effects when applied on CNS. 24 All these results could pinpoint a beneficial effect of reduced LysoPC(16:0) levels that argue against our claim that it marks an early SR risk, but although high levels of plaque LysoPC(16:0) are correlated with high plasma and plaque levels of Lp-PLA2, plasma LysoPC(16:0) levels are not.…”