Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

Abstract

The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

Keywords: J2 prostaglandins; UPP; mitochondria; neurodegeneration; neuroinflammation.

Figure 1

Prostanoid biosynthetic pathway. Arachidonic acid is converted via a two-step process (cyclooxygenation and hydroperoxidation) by cyclooxygenase enzymes COX-1 or COX-2 into the unstable prostaglandin PGH2. COX-1 is constitutively expressed while COX-2 is mostly an inducible enzyme that is upregulated under stress conditions. Non-steroidal anti-inflammatory drugs (NSAIDs) block the activities of both enzymes while Coxibs are selective COX-2 inhibitors. PGH2 is then converted to prostanoid products (PGE2, PGF2α, PGD2, PGI2, and TXA2) by specific prostaglandin synthases that differ in their cell type distribution. Of these products, PGD2 is highly unstable (estimated brain half-life of 1.1 min) resulting in the non-enzymatic formation of J2 prostaglandins.

Figure 2

Formation of prostaglandin J2 (PGJ2). Upon cell activation by mechanical trauma, cytokines, growth factors or other stressful stimuli, phospholipase A2 (PLA2) is recruited from the cytoplasm to intracellular membranes (nucleus or endoplasmic reticulum) to catalyze the hydrolysis of membrane sn-2 glycerophospholipids releasing arachidonic acid (AA, dark green). AA is converted by COX-1 or COX-2 to PGH2 (medium green) which is then converted to PGD2 (light green) by PGD synthase. PGD2 undergoes a non-enzymatic dehydration (–H₂O) to biologically active PGJ2 (yellow). PGJ2 can be localized to exosomes, to transport systems or to nuclear receptors to mediate its function.

Figure 3

Generation of J2 prostaglandins. PGJ2 is generated by non-enzymatic dehydration of PGD2. The J2 metabolites Δ12-PGJ2 and 15d-PGJ2 are formed from PGJ2 either by reactions catalyzed by human serum albumin (HSA) or by dehydration (–H₂O), respectively. Asterisks indicate α,β-unsaturated carbonyl groups.

Figure 4

Modes of action of J2 prostaglandins. PGJ2 and its metabolites exit the cell via diffusion or poorly defined transporters, and can enter cells or the nucleus via active transporters at the plasma or nuclear membranes. PGJ2 and its metabolites exert their actions by different mechanisms. They can bind to the DP2 receptor on the plasma membrane or to the peroxisomal proliferator activator receptor (PPARγ) at the nuclear membrane. Trafficking of PGJ2 and its metabolites in and out of cells can also occur via exosomes.

Figure 5

J2 prostaglandins interact directly with cellular proteins. J2 prostaglandins (shown for 15d-PGJ2) covalently modify selective proteins through Michael addition. Their α,β-unsaturated carbonyl groups (asterisks) react with free sulfhydryls (SH) in cysteines on glutathione and cellular proteins.

Figure 6

Potential mechanisms by which J2 prostaglandins promote neurodegeneration. During neuroinflammation PGJ2 (and its metabolites) are released from activated microglia and astrocytes. Free or exosome enclosed PGJ2 mediates the spread of neurodamage within the brain via intercellular uptake. PGJ2 also increases the levels of COX-2, thus activating a positive feedback loop that could mediate the transition from acute to chronic inflammation.

Figure 7

J2 prostaglandins target the ubiquitin proteasome pathway (UPP) and mitochondria. J2 prostaglandins affect the UPP by: (1) impairing the 26S proteasome by inducing oxidation of proteasome subunits, or promoting its disassembly, (2) inhibiting de-ubiquitinating enzymes (DUBs), and (3) covalently modifying specific active site cysteines on UPP components such as E1 activating enzymes, E2 conjugating enzymes, and some E3 ligases. J2 prostaglandins can also inhibit mitochondrial function by: (1) inhibiting NADH-ubiquinone reductase in complex I, (2) reducing membrane potential, (3) blocking fission, and (4) inducing the generation of reactive oxygen species (ROS) and apoptosis.