Neocortical and cerebellar developmental abnormalities in conditions of selective elimination of peroxisomes from brain or from liver

Abstract

Defects in the formation of the cerebral cortex and the cerebellum are a prominent feature of the peroxisome biogenesis disorder Zellweger syndrome and in mouse models for this disease. The aim of the present study was to investigate the impact of liver and brain peroxisomes on neurodevelopment by analyzing mice with tissue-selective elimination of peroxisomes. To this end, Pex5-loxP mice were bred with albumin/a-fetoprotein (Alfp)-Cre and nestin (Nes)-Cre mice. Local elimination of peroxisomes from the brain in Nes-Pex5 knockout mice caused a delay of cortical neuronal migration and of the formation of cerebellar folia and fissures. Migration of granule cells from the external granular layer was retarded, as was the polarization and branching of Purkinje cells, resulting in a less complex branching pattern and a smaller dendritic tree at P21. The AlfpPex5 knockout mice were affected differently, displaying a partial arrest of neuronal migration in the cerebral neopallium in the postnatal period despite of the incomplete elimination of peroxisomes from liver during embryonic development. Major abnormalities were seen in the formation of the cerebellum of these liver knockout mice, including hypotrophy, impaired foliation, a delay of granule cell migration, increased cell death, and stunted Purkinje cell arborization. In conclusion, these data demonstrate that absence of peroxisomal function both from liver and brain impairs cortical neuronal migration and maturation of the cerebellum, but different pathogenic mechanisms might be involved.

Absence of Functional Peroxisomes from Mouse CNS Causes Dysmyelination and Axon Degeneration

“…Nestin-Cre (Nes-Cre) mice (Tronche et al, 1999) were mated with Pex5 FL/ϩ mice (Baes et al, 2002), and selected Nes-Cre Pex5 FL/ϩ offspring were crossed with Pex5 FL/FL mice to obtain Nes-Cre Pex5 FL/FL , further denoted as Nes-Pex5 knock-out mice (Krysko et al, 2007).…”

“…The generation of Nes-Pex5 knock-out mice and demonstration of Pex5 inactivation, which was completed between embryonic day 14.5 (E14.5) and E18.5, were described previously (Baes et al, 2002;Krysko et al, 2007). Newborn Nes-Pex5 knock-out pups were indistinguishable from control littermates but they displayed a marked postnatal growth retardation ( Fig.…”

“…Plasmalogens, a subclass of etherphospholipids that were reduced by 65% in brain of newborn Nes-Pex5 knock-out mice (Krysko et al, 2007), were more profoundly depleted in 5-month-old mice (Table 1). Conversely, levels of the very long chain fatty acid (VLCFA) C 26:0 were threefold increased at birth and sixfold in adulthood (Table 1).…”

“…Indeed, we showed that elimination of functional peroxisomes from fetal liver, by ␣-fetoprotein promoter driven Cre recombination of the Pex5 gene, had a dramatic and permanent impact on the formation of cortex and cerebellum. In contrast, local ablation of Pex5 from the CNS using Nestin-Cre mice, only caused delays in neuronal positioning during the prenatal and early postnatal period (Krysko et al, 2007). Because a substantial fraction of the NesPex5 knock-out mice survived into early adulthood, we have further exploited this model to investigate the long-term effects of a complete deficiency of functional peroxisomes within the CNS.…”

Psychosine-induced alterations in peroxisomes of twitcher mouse liver

“…In addition, peroxisomes produce and detoxify hydrogen peroxide generated by the many oxidases that contain [17], and participate in the biosynthesis of important structural membrane constituents, such as the n-3 polyunsaturated fatty acid docosahexaenoic acid and plasmalogens [18,19]. Furthermore, their importance is underscored by the identification of fatal neurological diseases as a result of alterations of peroxisome biogenesis or proteins dysfunction [20,21]; and the role that peroxisomal metabolism play in brain myelination [22][23][24], brain cell homeostasis [25][26][27], and inflammation [28][29][30].…”