Impaired membrane traffic in defective ether lipid biosynthesis

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Thai T, Rodemer C, Jauch A, Hunziker A, Moser A, Gorgas K, and Just WW. (2001) Impaired membrane traffic in defective ether lipid biosynthesis. Human Molecular Genetics, 10(2): 127-136

Peroxisomal disorders are often the result of inheriting an autosomal recessive trait causing either a defective peroxisomal protein or disrupting peroxisomal assembly, in turn inhibiting plasmalogen biosynthesis. Plasmalogens are a class of lipids that contain a vinyl-ether bond at sn-1, and a deficiency is thought to be involved in a number of diseases. Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic condition that occurs from an inability to produce plasmalogens through defective peroxisomal activity. At the time this article was written in 2001, the importance of plasmalogens was only beginning to be understood, however roles had been suggested in membrane fluidity, protecting against oxidative stress, signal transduction, and membrane fusion being described. Today, after an additional 20 years of research there is more certainty and understanding behind these assertions. Thai et al described the peroxisomal disorders experienced by four young patients and looked at the structural differences seen in caveolae, clathrin coated pits, endoplasmic reticulum (ER), and golgi cisternae.

All the patients included in the study had RCDP; three of the patients (Patients 1-3) were found to have mutations in dihydroxyacetonephosphate acyltransferase (GNPAT) and one (Patient 4) was deficient in alkyl dihydroxyacetonephosphate synthase (AGPS), the genes encoding two enzymes found in peroxisomes that are essential for plasmalogen biosynthesis. Additionally, they were able to use partial sequences of the genes to determine the chromosomal location of GNPAT and AGPS. Human skin fibroblasts (hSFs) were isolated from all four patients to analyze the activity of both proteins within the samples. Patients 1-3 that were found to have undetectable levels of GNPAT activity, while the activity of AGPS was undetectable in Patient 4. The activity of the other protein in the patients (AGPS in Patients 1-3 and GNPAT in Patient 4) was not greatly altered.

As it was known that plasmalogens are located within the plasma membrane and have many important structural roles, phenotypic changes were also investigated in the cells. Caveolae, small invaginations along the plasma membrane important for endocytosis, were found to be reduced in number and organization in the mutant lines compared to the controls where many were found very close together and arranged in line. The caveolae found in the mutants were also ~30% smaller than the controls and the distance between two was increased by ~250%. The distribution of clathrin, a protein that helps form vesicles, was also studied. The control cells showed the standard omega-shaped clathrin-coated pits along the plasma membrane with 400nm extensions seen infrequently, while the mutant cell line pits were quite enlarged and often made of multiple clathrin patches that would extend up to 2µm in diameter.

The ER and the golgi apparatus are two organelles involved in intracellular vesicular trafficking. The cisternae of both organelles showed structural alterations in the mutant cells. Calreticulin and collagen type I were used as markers for the ER and the golgi, respectively, and both were found to be more intense in the mutant lines, indicating their possible accumulation due to poor membrane trafficking. As well, the ER cisternae was very dilated while the golgi apparatus was extremely extended when compared to the typical length of golgi in the control cells.

Thai et al demonstrated that plasmalogen deficient membranes have seriously altered composition, affecting the ability for the cell to form caveolae and clatharin-coated pits, both critical for endocytosis. If cells cannot transport materials into, out of, or within the cell this will prevent cell communication and many different proteins and macromolecules from being formed. These early case studies describing the characteristics of peroxisomal disorders and the structural defects present have provided insights into the roles of plasmalogens, which have helped understand their role in other diseases associated with a plasmalogen deficiency including Alzheimer’s and Parkinson’s disease.