Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport
Fatima Ferreirinha, … , Andrea Ballabio, Elena I. Rugarli
Fatima Ferreirinha, … , Andrea Ballabio, Elena I. Rugarli
Published January 15, 2004
Citation Information: J Clin Invest. 2004;113(2):231-242. https://doi.org/10.1172/JCI20138.
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Article Neuroscience

Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

Abstract

In several neurodegenerative diseases, axonal degeneration occurs before neuronal death and contributes significantly to patients’ disability. Hereditary spastic paraplegia (HSP) is a genetically heterogeneous condition characterized by selective degeneration of axons of the corticospinal tracts and fasciculus gracilis. HSP may therefore be considered an exemplary disease to study the local programs mediating axonal degeneration. We have developed a mouse model for autosomal recessive HSP due to mutations in the SPG7 gene encoding the mitochondrial ATPase paraplegin. Paraplegin-deficient mice are affected by a distal axonopathy of spinal and peripheral axons, characterized by axonal swelling and degeneration. We found that mitochondrial morphological abnormalities occurred in synaptic terminals and in distal regions of axons long before the first signs of swelling and degeneration and correlated with onset of motor impairment during a rotarod test. Axonal swellings occur through massive accumulation of organelles and neurofilaments, suggesting impairment of anterograde axonal transport. Retrograde axonal transport is delayed in symptomatic mice. We speculate that local failure of mitochondrial function may affect axonal transport and cause axonal degeneration. Our data suggest that a timely therapeutic intervention may prevent the loss of axons.

Authors

Fatima Ferreirinha, Angelo Quattrini, Marinella Pirozzi, Valentina Valsecchi, Giorgia Dina, Vania Broccoli, Alberto Auricchio, Fiorella Piemonte, Giulia Tozzi, Laura Gaeta, Giorgio Casari, Andrea Ballabio, Elena I. Rugarli

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Figure 1

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Strategy of the Spg7 knockout. (a) The top diagram shows the WT genomic ...
Strategy of the Spg7 knockout. (a) The top diagram shows the WT genomic map comprising the first three Spg7 exons (ex), the position of the two external probes, and the EcoRV sites used for Southern analysis. On the bottom is a schematic representation of the targeting construct and the resulting targeted locus. Following homologous recombination, the insertion disrupted part of the promoter region and the first two exons of the gene, comprising the initiation methionine codon and most of the mitochondrial leader sequence. (b) Southern analysis of the first litter using the 5′ probe. The WT fragment is 18 kb, whereas the fragment corresponding to the targeted locus is 10 kb. (c) RT-PCR analysis on total embryo cDNA using oligonucleotides spanning exons 3 and 4, which were not targeted by the deletion, demonstrates that the Spg7 transcript is lacking in knockout mice. (d) Western blot analysis on mitochondrial proteins isolated from spinal cords of WT and knockout mice shows the absence of paraplegin in Spg7–/– animals.