Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport
Fátima FerreirinhaAngelo QuattriniMarinella PirozziValentina ValsecchiGiorgia DinaVania BroccoliAlberto AuricchioFiorella PiemonteGiulia TozziLaura GaetaGiorgio CasariAndrea BallabioElena I. Rugarli
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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.Keywords:
Axoplasmic transport
Axonal Degeneration
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Hereditary Spastic Paraplegia
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Analysis of slow axonal transport in the sciatic and primary visual systems of rats with streptozotocin-induced diabetes of 4-6 weeks duration showed impairment of the transport of neurofilament subunits, tubulin, actin, and a 30- and a 60-kDa polypeptide in both systems. The degree of impairment was not uniform. Transport of polypeptide constituents of the slow component b, such as the 30- and 60-kDa polypeptides, appeared to be more severely affected than the transport of constituents of the slow component a, such as neurofilaments. Morphometric analysis of sciatic axons revealed a proximal increase and a distal decrease of axonal cross-sectional area. It is proposed that impairment of axoplasmic transport and changes of axonal size are related. Transport impairment results in a larger number of neurofilaments, microtubules, and other polypeptides in the proximal region of the axon, which increases in size, whereas fewer neurofilaments, microtubules, and other polypeptides reach the distal axons that show a size decrease. Such changes in axonal transport and area are likely to occur in other diabetic animal models and in human diabetes.
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In axons, cytoskeletal constituents move by slow transport. However, it remains controversial whether axonal neurofilaments are dynamic structures in which only subunits are transported or whether filaments assemble in the proximal axon and are transported intact as polymers to the axon terminus. To investigate the form neurofilament proteins take during transport, neurons of transgenic mice lacking axonal neurofilaments were infected with a recombinant adenoviral vector encoding epitope-tagged neurofilament M. Confocal and electron microscopy revealed that the virally encoded neurofilament M was transported in unpolymerized form along axonal microtubules. Thus, neurofilament proteins are probably transported as subunits or small oligomers along microtubules, which are major routes for slow axonal transport.
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β,β′-Iminodipropionitrile (IDPN) administration prevented normal slow axonal transport of [ 35 S]methionine- or [ 3 H]leucine-labeled proteins in rat sciatic motor axons. Ultrastructural and electrophoretic studies showed that the neurofilament triplet proteins in particular were retained within the initial 5 millimeters of the axons, resulting in neurofilament-filled axonal swellings. Fast anterograde and retrograde axonal transport were not affected. The IDPN thus selectively impaired slow axonal transport. The neurofibrillary pathology in this model is the result of the defective slow transport of neurofilaments.
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We have investigated the axonal transport of neurofilament protein in cultured neurons by constricting single axons with fine glass fibers. We observed a rapid accumulation of anterogradely and retrogradely transported membranous organelles on both sides of the constrictions and a more gradual accumulation of neurofilament protein proximal to the constrictions. Neurofilament protein accumulation was dependent on the presence of metabolic substrates and was blocked by iodoacetate, which is an inhibitor of glycolysis. These data indicate that neurofilament protein moves anterogradely in these axons by a mechanism that is directly or indirectly dependent on nucleoside triphosphates. The average transport rate was estimated to be at least 130 μm/h (3.1 mm/d), and ∼90% of the accumulated neurofilament protein remained in the axon after detergent extraction, suggesting that it was present in a polymerized form. Electron microscopy demonstrated that there were an abnormally large number of neurofilament polymers proximal to the constrictions. These data suggest that the neurofilament proteins were transported either as assembled polymers or in a nonpolymeric form that assembled locally at the site of accumulation. This study represents the first demonstration of the axonal transport of neurofilament protein in cultured neurons.
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