Modeling the cell biology of PEX11β deficiency during human neurogenesis

Peroxisomes are highly specialized organelles that are important for various metabolic functions, including {beta}-oxidation of very-long-chain fatty acids and the synthesis of plasmalogens. Mutations in peroxisomal biogenesis proteins cause Zellweger spectrum disorders (ZSD), rare multisystem disorders often associated with neurological phenotypes. Unlike other peroxisome biogenesis proteins, PEX11{beta} regulates peroxisomal fission, and PEX11{beta} mutations result in milder metabolic phenotypes but persistent neurodevelopmental abnormalities, suggesting a role for PEX11{beta} in neurodevelopment. To model PEX11{beta} deficiency during human neurogenesis, we generated PEX11{beta} knockout human iPSCs and differentiated them into neural progenitors and neural rosettes. PEX11{beta} loss caused elongated peroxisomal morphology, reduced fission, and impaired recruitment of fission proteins, without affecting mitochondrial morphology or respiration. Elongated peroxisomal morphology was independent of the peroxisome-endoplasmic reticulum tether. Lipidomic analysis revealed reduced ether-linked phospholipids in PEX11{beta}-deficient neural progenitors, suggesting impaired peroxisomal function. Finally, PEX11{beta} deficiency led to increased neural rosette lumen size and neural progenitor number.