Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency
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 n...
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doaj-314a5893f8454d6ca8748200cde959502021-03-22T12:44:32ZengElsevierNeurobiology of Disease1095-953X2016-10-0194157168Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiencyStephanie De Munter0Simon Verheijden1Esther Vanderstuyft2Ana Rita Malheiro3Pedro Brites4David Gall5Serge N. Schiffmann6Myriam Baes7KU Leuven – University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, BelgiumKU Leuven – University of Leuven, Department of Clinical and Experimental Medicine, TARGID, B-3000 Leuven, BelgiumKU Leuven – University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, BelgiumInstituto de Biologia Molecular e Celular – IBMC, Instituto de Inovação e Investigação em Saúde, University of Porto, Nerve Regeneration group, 4200-135 Porto, PortugalInstituto de Biologia Molecular e Celular – IBMC, Instituto de Inovação e Investigação em Saúde, University of Porto, Nerve Regeneration group, 4200-135 Porto, PortugalULB - Faculté de Médecine, Campus Erasme, – Laboratory of Neurophysiology, ULB-Neuroscience Institute, B-1070 Brussels, BelgiumULB - Faculté de Médecine, Campus Erasme, – Laboratory of Neurophysiology, ULB-Neuroscience Institute, B-1070 Brussels, BelgiumKU Leuven – University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, B-3000 Leuven, Belgium; Corresponding author at: Laboratory for Cell Metabolism, Faculty of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg O/N2, Herestraat 49, B 3000 Leuven, Belgium.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 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 β-oxidation in neural cells.http://www.sciencedirect.com/science/article/pii/S0969996116301528Peroxisomesβ-OxidationMultifunctional protein-2Purkinje cellAtaxiaAxonal swellings |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stephanie De Munter Simon Verheijden Esther Vanderstuyft Ana Rita Malheiro Pedro Brites David Gall Serge N. Schiffmann Myriam Baes |
spellingShingle |
Stephanie De Munter Simon Verheijden Esther Vanderstuyft Ana Rita Malheiro Pedro Brites David Gall Serge N. Schiffmann Myriam Baes Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency Neurobiology of Disease Peroxisomes β-Oxidation Multifunctional protein-2 Purkinje cell Ataxia Axonal swellings |
author_facet |
Stephanie De Munter Simon Verheijden Esther Vanderstuyft Ana Rita Malheiro Pedro Brites David Gall Serge N. Schiffmann Myriam Baes |
author_sort |
Stephanie De Munter |
title |
Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency |
title_short |
Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency |
title_full |
Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency |
title_fullStr |
Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency |
title_full_unstemmed |
Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency |
title_sort |
early-onset purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2016-10-01 |
description |
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 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 β-oxidation in neural cells. |
topic |
Peroxisomes β-Oxidation Multifunctional protein-2 Purkinje cell Ataxia Axonal swellings |
url |
http://www.sciencedirect.com/science/article/pii/S0969996116301528 |
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