PEX11β Deficiency Is Lethal and Impairs Neuronal Migration but Does Not Abrogate Peroxisome Function

Abstract

Zellweger syndrome is a lethal neurological disorder characterized by severe defects in peroxisomal protein import. The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the other Zellweger syndrome phenotypes, including neuronal migration defects, hypotonia, a developmental delay, and neonatal lethality. These phenotypes are also manifested in mouse models of Zellweger syndrome generated by disruption of the PEX5 or PEX2 gene. Here we show that mice lacking peroxisomal membrane protein PEX11β display several pathologic features shared by these mouse models of Zellweger syndrome, including neuronal migration defects, enhanced neuronal apoptosis, a developmental delay, hypotonia, and neonatal lethality. However, PEX11β deficiency differs significantly from Zellweger syndrome and Zellweger syndrome mice in that it is not characterized by a detectable defect in peroxisomal protein import and displays only mild defects in peroxisomal fatty acid β-oxidation and peroxisomal ether lipid biosynthesis. These results demonstrate that the neurological pathologic features of Zellweger syndrome can occur without peroxisomal enzyme mislocalization and challenge current models of Zellweger syndrome pathogenesis.

We thank the Johns Hopkins University Transgenic Core Facility for blastocyst injections and generation of chimeric animals, Ann and Hugo Moser for the use of their laboratory for biochemical experiments, and Stephanie Mihalik and Paul Watkins for help with the peroxisomal α- and β-oxidation activity measurements.

This work was supported by grants from the National Institutes of Health to S.J.G. (DK59479) and D.V. (HD10981). D.V. is an investigator of the Howard Hughes Medical Institute. E.B. was supported by a Max-Kade Scholarship (Max-Kade Foundation, New York, N.Y., and Deutsche Forschungsgemeinschaft).