RCDP Mouse model projects
RCDP mouse model
Rhizomelic Chondrodysplasia Punctata (RCDP) is a heterogeneous group of peroxisomal disorders resulting from genetic defects in plasmalogen biosynthesis. In our lab we generated a series of Pex7 deficient mouse models (mild, intermediate and severe) that mimics the spectrum of disease severity in human RCDP. We used Pex7 deficient mouse models to better understand the consequence of plasmalogen deficiency caused by RCDP on the nervous and respiratory systems and to effectively establish preclinical endpoints that could be used to test therapeutic intervention.
Genotype-phenotype correlation and neurobehavioral characterization of RCDP mouse models
In the nervous system, plasmalogens (PL) have a critical role in myelin formation and physiological function. In this project we characterized the baseline neurological phenotype (using histology, biochemical and behavioral assessments) in Pex7 deficient mouse series in order to better understand the role of PL deficiency in the development of tissue pathology. Our results revealed that the genotype severity of the Pex7 models correlated with the levels of peroxisome metabolites: plasmalogens, C26:0 VLCFA and phytanic acid. We found a significant correlation between the severity of Pex7 genotype and survival rates, growth, brain myelin content and extent of loss of cerebellar Purkinje cells in Pex7 deficient mice. Behavioral assessment of all Pex7 deficient mice showed comparable hyperactivity in the open field environment. This hyperactive phenotype correlated with reduced levels of brain neurotransmitters in our Pex7 deficient mouse series.
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Cross-sectional slice of a wild-type mouse cerebellum stained with anti-calbindin antibody which is a marker for purkinje cells. Images from Grace Carter and Brittany Pounder, 2018.
Immunohistochemical studies of lungs of wild type control mice (upper panel) and of Pex7 hypomorphic mice (bottom panel). The left column shows the lung cellular architecture (Hematoxylin and Eosin stain) and the right column shows lung surfactant distribution (anti-prosurfactant protein C (proSP-C) antibody). Images from Wei Cui, current member of our lab.
Characterizing the biochemical, histological and functional phenotypes of the respiratory system in RCDP mouse models.
In the respiratory system, plasmalogens are important components of surfactant molecule that is secreted by type II alveolar cells to reduce surface tension. In this project we are investigating the abnormalities in lung structure (histology) and function that are caused by plasmalogen deficiency in RCDP mouse models. Also we will perform lipid analysis using LC/MSMS to measure plasmalogen species and C26:0 VLCFA in the lung tissues and bronchial secretions from pex7 deficient mice. For functional assessment, we will evaluate the forced oscillation measurements using a computer-controlled piston ventilator system (flexiVent; SCIREQ Inc, Montreal, QC, Canada).
Plasmalogens replacement therapy improves plasmalogens and normalizes the abnormal hyperactive behavior in RCDP mouse model.
We studied the efficacy of oral synthetic PL compounds (PPI-1040) to improve PL levels and ameliorate the hyperactivity phenotypes of Pex7 deficient mice using the intermediate (hypomorphic) model. We found that after 4-week treatment, plasmalogen levels were significantly increased in blood and various peripheral tissues. While we did not measure any improvement in plasmalogen levels in brain tissue, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7 deficient mice. Thus, PPI-1040 represents a novel therapeutic option for augmenting PL levels in patients with RCDP, and potentially individuals with secondary plasmalogen deficiency states, such as Alzheimer’s and Parkinson’s diseases.
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Chemical structures of synthetic plasmalogens. Published in Fallatah, W., et al (2020). DMM Disease Models and Mechanisms, 13(1). https://doi.org/10.1242/dmm.042499