title: Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency.
abstract: 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.
authors.affiliation: KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium. Electronic address: Stephanie.Demunter@pharm.kuleuven.be.
authors.forename: Stephanie
authors.initials: S
authors.lastname: De Munter
authors.affiliation: KU Leuven - University of Leuven, Department of Clinical and Experimental Medicine, TARGID, B-3000 Leuven, Belgium. Electronic address: Simon.Verheijden@med.kuleuven.be.
authors.forename: Simon
authors.initials: S
authors.lastname: Verheijden
authors.affiliation: KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium. Electronic address: Esther.Vanderstuyft@gmail.com.
authors.forename: Esther
authors.initials: E
authors.lastname: Vanderstuyft
authors.affiliation: Instituto de Biologia Molecular e Celular - IBMC, Instituto de Inovação e Investigação em Saúde, University of Porto, Nerve Regeneration group, 4200-135 Porto, Portugal. Electronic address: Ana.malheiro@ibmc.up.pt.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Malheiro
authors.affiliation: Instituto de Biologia Molecular e Celular - IBMC, Instituto de Inovação e Investigação em Saúde, University of Porto, Nerve Regeneration group, 4200-135 Porto, Portugal. Electronic address: Dgall@ulb.ac.be.
authors.forename: Pedro
authors.initials: P
authors.lastname: Brites
authors.affiliation: ULB - Faculté de Médecine, Campus Erasme, - Laboratory of Neurophysiology, ULB-Neuroscience Institute, B-1070 Brussels, Belgium. Electronic address: Sschiffm@ulb.ac.be.
authors.forename: David
authors.initials: D
authors.lastname: Gall
authors.affiliation: ULB - Faculté de Médecine, Campus Erasme, - Laboratory of Neurophysiology, ULB-Neuroscience Institute, B-1070 Brussels, Belgium. Electronic address: Pedro.Brites@ibmc.up.pt.
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
authors.affiliation: KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium. Electronic address: Myriam.Baes@pharm.kuleuven.be.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D018345:Mice, Knockout; D064029:Peroxisomal Multifunctional Protein-2 / Q000172:deficiency / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
chemical_list: C491288:Hsd17b4 protein, mouse; D064029:Peroxisomal Multifunctional Protein-2
keywords: Ataxia; Axonal swellings; Climbing fiber; Electrophysiology; Multifunctional protein-2; Parallel fiber; Peroxisomes; Purkinje cell; β-Oxidation