title: Central serotonergic neuron deficiency in a mouse model of Zellweger syndrome.
abstract: Zellweger syndrome (ZS) is a severe peroxisomal disorder caused by mutations in peroxisome biogenesis, or PEX, genes. A central hallmark of ZS is abnormal neuronal migration and neurodegeneration, which manifests as widespread neurological dysfunction. The molecular basis of ZS neuropathology is not well understood. Here we present findings using a mouse model of ZS neuropathology with conditional brain inactivation of the PEX13 gene. We demonstrate that PEX13 brain mutants display changes that reflect an abnormal serotonergic system - decreased levels of tryptophan hydroxylase-2, the rate-limiting enzyme of serotonin (5-hydroxytryptamine, 5-HT) synthesis, dysmorphic 5-HT-positive neurons, abnormal distribution of 5-HT neurons, and dystrophic serotonergic axons. The raphe nuclei region of PEX13 brain mutants also display increased levels of apoptotic cells and reactive, inflammatory gliosis. Given the role of the serotonergic system in brain development and motor control, dysfunction of this system would account in part for the observed neurological changes of PEX13 brain mutants.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Qld, Australia; School of Biomolecular and Physical Sciences, Griffith University, Qld, Australia.
authors.forename: R S
authors.initials: RS
authors.lastname: Rahim
authors.affiliation: Griffith Health Institute, School of Medical Science, Griffith University, Qld, Australia.
authors.forename: A C B
authors.initials: AC
authors.lastname: Meedeniya
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Qld, Australia; School of Biomolecular and Physical Sciences, Griffith University, Qld, Australia. Electronic address: d.crane@griffith.edu.au.
authors.forename: D I
authors.initials: DI
authors.lastname: Crane
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D009154:Mutation; D015213:Neuroimmunomodulation / Q000502:physiology; D020675:Peroxisomes / Q000378:metabolism; D059326:Serotonergic Neurons / Q000378:metabolism / Q000473:pathology*; D014365:Tryptophan Hydroxylase / Q000172:deficiency; D015211:Zellweger Syndrome / Q000378:metabolism / Q000473:pathology*
chemical_list: D008565:Membrane Proteins; C491106:Pex13 protein, mouse; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: PEX13 brain mutant; Zellweger syndrome; apoptosis; gliosis; raphe nuclei; serotonin