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

• Main Authors: Stephanie De Munter, Simon Verheijden, Esther Vanderstuyft, Ana Rita Malheiro, Pedro Brites, David Gall, Serge N. Schiffmann, Myriam Baes
• Format: Article
• Language: English
• Published: Elsevier 2016-10-01
• Series: Neurobiology of Disease
• Subjects: Peroxisomes; β-Oxidation; Multifunctional protein-2; Purkinje cell; Ataxia; Axonal swellings
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996116301528

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.