Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency

NEUROBIOLOGY OF DISEASE

卷:94

Article

De Munter, Stephanie¹  Verheijden, Simon²  Vanderstuyft, Esther¹  Malheiro, Ana Rita³  Brites, Pedro³  Gall, David⁴  Schiffmann, Serge N.⁴  Baes, Myriam¹ 

[1] Univ Leuven, KU Leuven, Dept Pharmaceut & Pharmacol Sci, Cell Metab, B-3000 Leuven, Belgium

[2] Univ Leuven, KU Leuven, Dept Clin & Expt Med, TARGID, B-3000 Leuven, Belgium

[3] Univ Porto, IBMC, Inst Inovacao & Invest Saude, Nerve Regenerat Grp, P-4200135 Oporto, Portugal

[4] ULB Neurosci Inst, ULB Fac Med, Neurophysiol Lab, Campus Erasme, B-1070 Brussels, Belgium

关键词: Peroxisomes;    beta-Oxidation;    Multifunctional protein-2;    Purkinje cell;    Ataxia;    Axonal swellings;    Electrophysiology;    Climbing fiber;    Parallel fiber;   

DOI  :  10.1016/j.nbd.2016.06.012

来源: Elsevier

【 摘 要 】

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 beta-oxidation. At the age of 4 weeks, 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 beta-oxidation in neural cells. (C) 2016 Elsevier Inc. All rights reserved.

【 授权许可】

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