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

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.

Pubmed ID: 14722615


  • Ferreirinha F
  • Quattrini A
  • Pirozzi M
  • Valsecchi V
  • Dina G
  • Broccoli V
  • Auricchio A
  • Piemonte F
  • Tozzi G
  • Gaeta L
  • Casari G
  • Ballabio A
  • Rugarli EI


The Journal of clinical investigation

Publication Data

January 14, 2004

Associated Grants

  • Agency: Telethon, Id: GGP030310
  • Agency: NINDS NIH HHS, Id: R01 NS-38713-01
  • Agency: Telethon, Id: TGM03S01
  • Agency: Telethon, Id: TGM06S01

Mesh Terms

  • Adenosine Triphosphate
  • Animals
  • Axons
  • Biological Transport
  • Blotting, Southern
  • Blotting, Western
  • DNA, Complementary
  • Electron Transport
  • Female
  • Genotype
  • Metalloendopeptidases
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Models, Genetic
  • Muscles
  • Mutation
  • Neurodegenerative Diseases
  • Phenotype
  • Recombination, Genetic
  • Spastic Paraplegia, Hereditary
  • Spinal Cord
  • Time Factors