Faust P L, Banka D, Siriratsivawong R, Ng V G, Wikander T M
Department of Pathology, Columbia University, New York, New York 10032, USA.
J Inherit Metab Dis. 2005;28(3):369-83. doi: 10.1007/s10545-005-7059-y.
Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes. The PEX2-/- mouse model for Zellweger syndrome has enabled us to evaluate the role of peroxisomes in the development and functioning of the nervous system. These studies have shown that, in addition to disturbances in neuronal migration in developing cerebral cortex and cerebellum, defects in neuronal differentiation, proliferation and survival may also contribute to the CNS malformations. However, owing to the multiorgan dysfunction in peroxisomal disorders, it has been difficult to clearly define an intrinsic role for the peroxisome in brain cells. The use of several in vitro cell culture assays to evaluate the migration and differentiation of cerebellar neurons demonstrates a persistence of defects in peroxisome-deficient neurons. The absence of potential systemically derived, extrinsic factors in these in vitro systems indicates that CNS intrinsic defects contribute to the pathogenesis of disease in these disorders. However, bile acid treatment also increases the survival and growth of PEX2-/- mice and improves some aspects of cerebellar development, indicating that extrinsic factors also affect the developing peroxisome-deficient brain. Therefore, the final phenotype of nervous system dysfunction in peroxisomal disorders will reflect a combination of both CNS intrinsic and extrinsic factors.
过氧化物酶体生物发生障碍中，泽韦格综合征最为严重，因缺乏功能性过氧化物酶体，导致与中枢神经系统（CNS）神经元迁移异常相关的严重神经功能障碍。泽韦格综合征的PEX2基因敲除小鼠模型使我们能够评估过氧化物酶体在神经系统发育和功能中的作用。这些研究表明，除了发育中的大脑皮层和小脑中神经元迁移紊乱外，神经元分化、增殖和存活缺陷也可能导致中枢神经系统畸形。然而，由于过氧化物酶体疾病存在多器官功能障碍，很难明确过氧化物酶体在脑细胞中的内在作用。使用几种体外细胞培养试验来评估小脑神经元的迁移和分化，结果表明过氧化物酶体缺陷神经元中存在持续性缺陷。这些体外系统中不存在潜在的全身来源的外在因素，这表明中枢神经系统内在缺陷导致了这些疾病的发病机制。然而，胆汁酸治疗也能提高PEX2基因敲除小鼠的存活率和生长率，并改善小脑发育的某些方面，这表明外在因素也会影响发育中的过氧化物酶体缺陷大脑。因此，过氧化物酶体疾病中神经功能障碍的最终表型将反映中枢神经系统内在因素和外在因素的综合作用。
