Peroxisomes are enzyme-containing membrane organelles that are involved in the detoxification of reactive oxygen species, the catabolism of very long chain fatty acids and the biosynthesis of plasmalogens. Patients with peroxisomal biogenesis disorders (PBD) show neurological defects ranging from the severe disease Zellweger syndrome that is lethal within six months of birth, to the progressive diseases of cerebellar ataxia and spinal ataxia. Despite the fact that neurological deficits can be observed at birth in some PBD patients, the embryological etiology of the disease has not been explored. Moreover, there are no effective therapies to prevent or ameliorate the neural degeneration that occurs in PBD patients. In mice we have identified a mutation in the peroxisomal gene Pex10. Biomarkers utilized for diagnosis of PBD in humans are similarly disrupted in the Pex10 mouse model. Moreover, Pex10 mutant mouse embryos show a progressive inability to move. Thus, our Pex10 mutant provides an excellent paradigm for the study of PBD neuropathology and the first vertebrate Pex10 model. Analysis of Pex10 mutant embryos shows defects in the connectivity between the motor nerves and the muscle. These preliminary data provide the basis for this R21 proposal to understand the embryological origin of the neurological deficits and to explore possible therapies to increase the lifespan and ameliorate the neuropathology in this peroxisomal animal model.
Aim 1 will characterize the novel Pex10 mouse mutant as a model for PBD progressive ataxia. We will test the hypothesis that alterations in peroxisomal function in the embryo inhibit termination of axons at the synapse which disrupts the connectivity of the locomotor circuit. We will determine whether the progressive embryonic locomotor loss results from defects in myelination, axon guidance and/or synapse function of the spinal neurons.
Aim 2 will provide the first definition of the peroxisomal proteome in the fetus and will determine the changes in the contents of the peroxisome in Pex10 mutants, in particular in the myelinating Schwann cells. Moreover, we will determine whether the point mutation in the PEX10 zinc RING finger disrupts ubiquitination activity, which could alter recycling of the peroxisomal receptor.
Aim 3 will use the Pex10 mouse model to evaluate possible therapeutic strategies to increase the lifespan and rescue the neuronal phenotypes in mutant mice. Overall these studies will provide the first insight into the embryological origin of PBD neuropathies and will seek to define potential therapies to alleviate the profound neurodegenerative defects that underlie peroxisomal diseases.
Peroxisomal biogenesis disorders (PBD) lead to severe neurological defects. Although the genes that regulate peroxisomal function are well-defined, it remains unclear how the neurological defects arise. In addition, there are no effective therapies to prevent or ameliorate the neural degeneration that occurs in PBD patients. The goal of this proposal is to use a mouse model of PBD to understand the embryological origin of the neuropathology and to begin to explore strategies that may in the future yield an effective preemptive therapy for patients with PBD.
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