Role and function of peroxisomes in neuroinflammation

Sarkar C and Lipinski MM. (2024) Role and function of peroxisomes in neuroinflammation. Cells

Peroxisomes are membrane enclosed organelles found in eukaryotic cells that are responsible for maintaining redox balance and producing enzyme catalase to break down hydrogen peroxide. In addition, peroxisomes are the location where biosynthesis of ether-phospholipids begins in the cell and is the site of lipid metabolism, including degradation of very-long-chain fatty acids by β-oxidation and branched-chain fatty acids by α-oxidation. The importance of peroxisomes was revealed when peroxisomal disorders, congenital diseases caused by deficiencies in peroxisomal proteins, were discovered. These were associated with severe pathological phenotypes such as neurological impairment, neurodegeneration, and neuroinflammation. Neuroinflammation can result from neuronal injury, stress, infection, and disease, which can lead to the proliferation and activation of central nervous system (CNS) microglia and astrocytes, and the migration of peripheral macrophages to the CNS. Peroxisomes have many roles in immune cells and their inflammatory response, and the dysfunction of peroxisomes can trigger inflammation. Although peroxisomes have many functions in immune response that were discussed in the review article by Sarkar and Lipinski, this literature blog will focus on lipid synthesis, redox balance maintenance, and neuroinflammation in peroxisomal biogenesis disorders (PBDs).

Peroxisomes are the location for the initial steps of ether-phospholipid (ether-PLs) synthesis. Ether-PLs are a type of glycerophospholipids that contain an ether bond at the sn-1 position on the glycerol backbone. These can be split into two types: alkyl ether-PLs or alkenyl (or vinyl) ether-PLs and this is based on the unsaturation next to the ether bond. Alkenyl ether-PLs are also called plasmalogens and these contain a double bond next to the ether, making these lipids very important within lipid rafts, in cellular signaling, and allows them to act as an antioxidant. Ether-PLs make up almost 20% of the phospholipids in the brain and are a major constituent of myelin. The double bond in plasmalogens causes their side-chains to be more compact which adds structural rigidity to myelin. When ether-PLs homeostasis is altered, this can interfere with neuronal function and trigger neuroinflammation since plasmalogens have essential roles in regulating inflammatory responses. Also, when plasmalogens are supplied through a treatment, microglial activation can be effectively reduced, supporting their importance in inflammation regulation.

Peroxisomes are responsible for maintaining redox balance within cells through containing both radical oxygen species (ROS)-generating and ROS-degrading enzymes. Many of the enzymes within peroxisomes create hydrogen peroxide as a by-product which then needs to be broken down by one of the antioxidant enzymes in the organelle. When this balance is interrupted, it can lead to oxidative stress in the cell, which is associated with neuroinflammation. When neuroinflammation occurs, ROS are produced and this can trigger immune cells to respond by activating microglia or astrocytes.

Mutations in one or more peroxisomal proteins that leads to a disruption in peroxisomal activity result in peroxisomal disorders and these can be classified as either peroxisomal biogenesis disorders (PBDs) or single-peroxisomal protein deficiencies. This literature blog will only explore the PBDs. PBDs are the result of mutations in any of 13 PEX genes which encode proteins that act to import peroxisomal proteins to peroxisomal structures and the inability for this to occur alters peroxisomal assembly or prevents maturation. Some examples of PBDs are Rhizomelic chondrodysplasia punctata (RCDP) and Zellweger spectrum disorders (ZSDs) including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum’s disease (IRD). Neuroinflammation has not been studied in depth in humans with PBDs, but severe inflammatory responses have been associated in a patient with ZS with a mutation in PEX6 as well as animal models of ZSDs. Increased levels of proinflammatory cytokines and chemokines have been shown in brains of oligodendrocyte-specific Pex5-knockout mice. In addition, in neural-specific Pex5-knockout mice, activation of innate immune response was present and many proinflammatory markers were significantly increased in the brains of these mice.

Sarkar and Lipinski were interested in exploring the literature for the role of peroxisomes in neuroinflammation. They looked at the many roles that peroxisomes have in immune responses including peroxisomal β-oxidation, synthesis of ether-lipids, and peroxisomal redox metabolism, as well as their role in innate immune signaling during viral infection and neuroinflammation in peroxisomal disorders. Through all the data that has been gathered on peroxisomes and inflammation, it is clear that intact peroxisomal function is necessary to impede neuroinflammation. PBDs are not very common, however the authors note that it is also known that peroxisomal function reduces with age and this could be associated with neurodegeneration and increased neuroinflammation. Continued research into the role of peroxisomes in neuroinflammation and its protective abilities could help provide additional therapeutic targets for PBDs, neurodegeneration, and neuroinflammation.