A mouse model system to study peroxisomal roles in neurodegeneration of peroxisome biogenesis disorders

Abe Y, Tamura S, Honsho M, and Fujiki Y. “A mouse model system to study peroxisomal roles in neurodegeneration of peroxisome biogenesis disorders.” Peroxisome Biology: Experimental Models, Peroxisomal Disorders and Neurological Diseases, edited by Gérard Lizard, Springer Nature Switzerland AG, 2020, 119-143

At Med-Life Discoveries our research is primarily focused on rhizomelic chondrodysplasia punctata (RCDP), a rare disease characterized by severe dwarfism and cognitive deficits, however RCDP falls under the larger peroxisomal biogenesis disorder (PBD) umbrella. PBDs are a class of very rare diseases caused by defects in peroxisome biosynthesis or peroxisomal dysfunction. The peroxisome is responsible for cellular lipid metabolism, plasmalogen biosynthesis, myelin production, and metabolism of radical oxygen species, therefore when the organelle is unable to function properly the results are severe and affect all major organs in the body. In addition to RCDP, peroxisomal disorders also include Zellweger spectrum disorder (ZS), X-linked adrenoleukodystrophy, and Refsum disease. Since patients with these disorders experience neurodegenerative symptoms, animal models have been developed by disrupting Pex (the genes responsible for peroxisome biogenesis) expression either within the whole animal or tissue-specific to study the underlying molecular causes of the pathology.

The Pex genes that have been targeted to make animal models of PBDs are Pex2, Pex5, Pex10, Pex13 and Pex14. Similar to the human phenotype of ZS, these mouse models show growth defects, severe hypotonia, and a severely reduced lifespan. As well, during neuronal migration the ZS mouse model has an abnormal cortical plate and altered distribution of cells in the cortical plate, indicating a neuronal migration delay during embryonic development. This alteration of the cortical laminar structure is characteristic of ZS seen in humans. As well, demyelination is typical in patients with ZS but most of the Pex knockout mice do not live long enough for myelination to occur. However, in the Pex5 KO mouse demyelination began at 2 weeks of age and is present in the cerebellum at 3 and 6 weeks of age, indicating a destabilization of myelin in these mice.

To determine the mechanisms behind the phenotype of PBDs in more detail, mouse lines with tissue-specific knockdowns of the Pex5 or Pex13 genes were created. As a lot of the effects of PBDs are neurodegenerative, the central nervous system (CNS) was an obvious target. Although the CNS-targeted Pex knockdown result in mice with ataxia, dyskinesia, and memory impairments in addition to cortical neuronal migration delay, the effects are less severe than the full Pex KO mice. These mice survive to 5-6 weeks of age, indicating that potential inter-organ communication may compensate for the lack of peroxisomal activity in the CNS. In contrast, the liver-specific Pex KO show severe growth and developmental delays and ~80% die within the first 8 days, with all dying by 16 days. These mice show the same level of CNS morphological changes as the whole-body Pex KO animals. To further confirm the essential role of liver peroxisomes, when peroxisomes are reconstituted in the liver-specific Pex KO animals, an improvement in neuronal migration is seen in the cortex.

A number of animal models have been developed to study the spectrum of PBDs through knocking-out all peroxisomal function or function within specific tissues. These animal models provide an excellent resource to learn more about these very rare diseases and a better understanding of the types of therapies that could benefit PBD patients. This work has demonstrated the role of the peroxisome in neurological function, consistent with what is seen in RCDP and Alzheimer’s disease, and specifically provides further evidence that peroxisome activity in the liver may have a role in neurological development. There is a growing theory that plasmalogens synthesized in liver peroxisomes makes up the majority of the plasmalogens in the brain, and these findings support this. This knowledge also offers a potential peripheral target for therapeutics, avoiding the hurdle of needing to cross the blood brain barrier. Further work with these models will deliver necessary information for developing effective therapies regarding a specific target, what functions would drive improvement, and the type of therapy that would provide the greatest benefit.