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.
Ferreirinha
Fatima
F
Telethon Institute of Genetics and Medicine, Naples, Italy.
Quattrini
Angelo
A
Pirozzi
Marinella
M
Valsecchi
Valentina
V
Dina
Giorgia
G
Broccoli
Vania
V
Auricchio
Alberto
A
Piemonte
Fiorella
F
Tozzi
Giulia
G
Gaeta
Laura
L
Casari
Giorgio
G
Ballabio
Andrea
A
Rugarli
Elena I
EI
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
D018076:DNA, Complementary; D000255:Adenosine Triphosphate; D008666:Metalloendopeptidases; C491813:Spg7 protein, mouse; D000074183:ATPases Associated with Diverse Cellular Activities