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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

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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 5

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Mitochondrial abnormalities in paraplegin-deficient mice. (a) The spinal...
Mitochondrial abnormalities in paraplegin-deficient mice. (a) The spinal cord has an overall normal structure in a 4.5-month-old Spg7–/– mouse, but high magnification analysis shows hypertrophic mitochondria (b), sometimes with swollen, disorganized cristae (arrow) (c). Several mitochondrial abnormalities are identifiable in the spinal cord at 8 months of age: swollen mitochondria with cristae still readily identifiable (asterisk), onion-like arrangement of mitochondrial cristae (arrows) (d), gigantic mitochondrion with abnormally organized membrane compartments and abnormal tubular content (e), closely associated mitochondria (f), and swollen mitochondria in which cristae are displaced at the periphery of the organelle (g). (h) Spinal axon of a 12-month-old Spg7–/– mouse containing degenerating mitochondria. (i) At 15 months of age, mitochondria are swollen and show degenerative features. There is a drastic reduction in the number of cristae, which are distended. The deposition of dense deposits can be observed. Mitochondrial bridges are also evident (arrow). (j) Transverse section of the optic nerve of 22-month-old paraplegin-deficient mouse showing one hypertrophic mitochondrion extending a finger-like protrusion (mitochondrial “bridge”; arrow) into a neighboring mitochondrion, which shows features of swelling and degeneration. Bar represents 5 μm in a, 0.8 μm in b, c, f, g, and j, and 1 μm in d, e, h, and i.
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