Overcoming plasmalogen deficiency in peroxisomal disorders (PERescue)

Peroxisome biogenesis disorders (PBD) are a heterogeneous group of rare, but severe disorders that share a defect in the biosynthesis of peroxisomes, small organelles, which fulfil a variety of different metabolic functions. One of these functions is the synthesis of plasmalogens, a certain subgroup of phospholipids. As a consequence of peroxisome deficiency, also plasmalogens cannot be produced. Whereas in the severe forms of PBD other defects may prevail, the lack of plasmalogens accounts for a major part of the observed symptoms in some subgroups of PBD, especially the milder variants, which allow survival of the affected patients into adulthood, and a certain subform termed rhizomelic chondrodysplasia punctata (RCDP). Up to now, there is no therapy available that enables the restoration of plasmalogen levels in the brain, where the consequences of plasmalogen deficiency are most dramatic. In the present project we, in cooperation with international experts in the field of peroxisomes and PBD, aim to develop therapeutic strategies for use in mild PBD and RCDP by identifying lipid precursor substances that can enter the brain and replace plasmalogens there. By using a variety of in vitro and in vivo models, we plan to elucidate the molecular basis of the inability of previously applied plasmalogen precursors to restore plasmalogen levels in the brains of PBD patients and of mouse models for PBD and RCDP. Using this knowledge, we will, together with our Belgian and Dutch partners, design and generate modified lipids with optimized biochemical properties that should facilitate uptake into the brain. These compounds will be tested for their ability to restore brain plasmalogens in a plasmalogen-deficient mouse model. Altogether, this project, by combining the knowledge of various specialists in the field, opens novel therapeutic fields for individuals affected by mild PBD, and in particular RCDP, and could even be of benefit for a larger group of patients, as reductions in brain plasmalogens have been described also in other, more common diseases, like for example Alzheimers disease.

Overcoming plasmalogen deficiency in peroxisomal disorders All cellular membranes in the human body consist of a phospholipid bilayer. About 20 to 50 percent of these phospholipids are plasmalogens, specific phospholipids with unique biophysical properties. If our body cannot synthesize these lipids due to mutations, this leads to a severe group of disorders termed rhizomelic chondrodysplasia punctata. However, plasmalogens are not only reduced in these rare genetic conditions but also in more common disorders such as Alzheimer's disease. Thus, there is major interest in correcting the plasmalogen deficiency in the brain of affected people. The present project was part of an international collaboration project aiming at the identification of therapeutic strategies to overcome plasmalogen deficiency. It had already been known before that certain plasmalogen precursors can restore plasmalogens in peripheral tissues of mouse models upon oral treatment. Here, we used a genetically modified mouse model with plasmalogen deficiency and demonstrated that the treatment duration required for plasmalogen restoration after oral precursor treatment is highly tissue-dependent. Plasmalogen levels were most rapidly corrected in the liver, whereas restoration took slightly longer in cardiac tissue or erythrocytes. However, no change in plasmalogen levels was achieved in brain even after a 60-day treatment. Thus, plasmalogens appear not to pass the blood-brain barrier. We hypothesized that one or more of the major efflux transporters at the blood-brain barrier are responsible for the inability of plasmalogens to enter the brain. To investigate this question, we generated a new model lacking on one hand the plasmalogen synthesis and on the other hand the three major efflux transporters at the blood-brain barrier (Abcb1a, Abcb1b and Abcg2). However, also under these conditions, the precursor treatment rescued plasmalogen levels only in the periphery but not in the brain. Even additional pharmacological inhibition of further transporters did not change the import situation. Thus, we concluded that plasmalogens cannot pass the blood-brain barrier and this is not due to efflux transporters of the ABC family. Interestingly, we found that the blood-placenta barrier can partially be overcome by precursor treatment of pregnant dams, but again in an efflux tranporter-independent manner. Remarkably, in spite of the absence of a blood-brain barrier at early developmental stages, the restoration was not as good as in adult peripheral tissues in any fetal organ, but still much higher in fetal cardiac tissue than in fetal brain. Our investigations of plasmalogen transport are of particular importance in light of the current propagation of dietary plasmalogen treatment attempts in Alzheimer's disease.