title: 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.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Fatima
authors.initials: F
authors.lastname: Ferreirinha
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Marinella
authors.initials: M
authors.lastname: Pirozzi
authors.forename: Valentina
authors.initials: V
authors.lastname: Valsecchi
authors.forename: Giorgia
authors.initials: G
authors.lastname: Dina
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.forename: Giulia
authors.initials: G
authors.lastname: Tozzi
authors.forename: Laura
authors.initials: L
authors.lastname: Gaeta
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001692:Biological Transport; D015139:Blotting, Southern; D015153:Blotting, Western; D018076:DNA, Complementary / Q000378:metabolism; D004579:Electron Transport; D005260:Female; D005838:Genotype; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D008957:Models, Genetic; D009132:Muscles / Q000473:pathology; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics; D010641:Phenotype; D011995:Recombination, Genetic; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D000255:Adenosine Triphosphate; D008666:Metalloendopeptidases; C491813:Spg7 protein, mouse; D000074183:ATPases Associated with Diverse Cellular Activities