KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium.
KU Leuven - University of Leuven, Department of Clinical and Experimental Medicine, TARGID, B-3000 Leuven, Belgium.
Neurobiol Dis. 2016 Oct;94:157-68. doi: 10.1016/j.nbd.2016.06.012. Epub 2016 Jun 25.
The cerebellar pathologies in peroxisomal diseases underscore that these organelles are required for the normal development and maintenance of the cerebellum, but the mechanisms have not been resolved. Here we investigated the origins of the early-onset coordination impairment in a mouse model with neural selective deficiency of multifunctional protein-2, the central enzyme of peroxisomal β-oxidation. At the age of 4weeks, Nestin-Mfp2(-/-) mice showed impaired motor learning on the accelerating rotarod and underperformed on the balance beam test. The gross morphology of the cerebellum and Purkinje cell arborization were normal. However, electrophysiology revealed a reduced Purkinje cell firing rate, a decreased excitability and an increased membrane capacitance. The distribution of climbing and parallel fiber synapses on Purkinje cells was immature and was accompanied by an increased spine length. Despite normal myelination, Purkinje cell axon degeneration was evident from the occurrence of axonal swellings containing accumulated organelles. In conclusion, the electrical activity, axonal integrity and wiring of Purkinje cells are exquisitely dependent on intact peroxisomal β-oxidation in neural cells.
过氧化物酶体病中的小脑病变强调了这些细胞器对于小脑的正常发育和维持是必需的，但机制尚未解决。在这里，我们研究了多官能蛋白-2（过氧化物体β-氧化的中心酶）在神经选择性缺乏的小鼠模型中早期运动协调障碍的起源。在 4 周龄时，巢蛋白-Mfp2（-/-）小鼠在加速旋转棒上表现出运动学习受损，在平衡梁测试中表现不佳。小脑和浦肯野细胞树突分支的大体形态正常。然而，电生理学显示浦肯野细胞放电率降低、兴奋性降低和膜电容增加。攀附纤维和平行纤维突触在浦肯野细胞上的分布不成熟，并伴有棘突长度增加。尽管髓鞘正常，但浦肯野细胞轴突退化明显，轴突肿胀含有累积的细胞器。总之，浦肯野细胞的电活动、轴突完整性和布线对神经细胞中完整的过氧化物体β-氧化是极其依赖的。
