Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease
In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-06-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114000540 |
| _version_ | 1818336655336013824 |
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| author | Carla Andreia Teixeira Catarina Oliveira Miranda Vera Filipe Sousa Telma Emanuela Santos Ana Rita Malheiro Melani Solomon Gustavo H. Maegawa Pedro Brites Mónica Mendes Sousa |
| author_facet | Carla Andreia Teixeira Catarina Oliveira Miranda Vera Filipe Sousa Telma Emanuela Santos Ana Rita Malheiro Melani Solomon Gustavo H. Maegawa Pedro Brites Mónica Mendes Sousa |
| author_sort | Carla Andreia Teixeira |
| collection | DOAJ |
| description | In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in the CNS, and of neurons in dorsal root ganglia (DRG), occurred before the onset of demyelination. Despite the early axonal loss, and although in vitro Twitcher neurites degenerated over time, Twitcher DRG neurons displayed an initial neurite overgrowth and, following sciatic nerve injury, Twitcher axons were regeneration-competent, at a time point where axonopathy was already ongoing. Psychosine, the toxic substrate that accumulates in KD, induced lipid raft clustering. At the mechanistic level, TrkA recruitment to lipid rafts was dysregulated in Twitcher neurons, and defective activation of the ERK1/2 and AKT pathways was identified. Besides defective recruitment of signaling molecules to lipid rafts, the early steps of endocytosis and the transport of endocytic and synaptic vesicles were impaired in Twitcher DRG neurons. Defects in axonal transport, specifically in the retrograde component, correlated with decreased levels of dynein, abnormal levels of post-translational tubulin modifications and decreased microtubule stability. The identification of the axonal defects that precede demyelination in KD, together with the finding that Twitcher axons are regeneration-competent when axonopathy is already installed, opens new windows of action to effectively correct the neuropathology that characterizes this disorder. |
| first_indexed | 2024-12-13T14:42:46Z |
| format | Article |
| id | doaj.art-1e0c5975e49641b3b4dff45ec2c27d10 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T14:42:46Z |
| publishDate | 2014-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-1e0c5975e49641b3b4dff45ec2c27d102022-12-21T23:41:34ZengElsevierNeurobiology of Disease1095-953X2014-06-016692103Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's diseaseCarla Andreia Teixeira0Catarina Oliveira Miranda1Vera Filipe Sousa2Telma Emanuela Santos3Ana Rita Malheiro4Melani Solomon5Gustavo H. Maegawa6Pedro Brites7Mónica Mendes Sousa8Nerve Regeneration Group, IBMC — Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, PortugalNerve Regeneration Group, IBMC — Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal; ICBAS — Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Largo Prof. Abel Salazar, 2, 4099-003 Porto, PortugalNerve Regeneration Group, IBMC — Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal; ICBAS — Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Largo Prof. Abel Salazar, 2, 4099-003 Porto, Portugal; Corresponding author at: Nerve Regeneration Group, IBMC, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. Fax: +351 22 6099157.Nerve Regeneration Group, IBMC — Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, PortugalNerve Regeneration Group, IBMC — Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, PortugalMcKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAMcKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USANerve Regeneration Group, IBMC — Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, PortugalNerve Regeneration Group, IBMC — Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal; Corresponding author at: Nerve Regeneration Group, IBMC, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. Fax: +351 22 6099157.In Krabbe's disease (KD), a leukodystrophy caused by β-galactosylceramidase deficiency, demyelination and a myelin-independent axonopathy contributes to the severe neuropathology. Beyond axonopathy, we show that in Twitcher mice, a model of KD, a decreased number of axons both in the PNS and in the CNS, and of neurons in dorsal root ganglia (DRG), occurred before the onset of demyelination. Despite the early axonal loss, and although in vitro Twitcher neurites degenerated over time, Twitcher DRG neurons displayed an initial neurite overgrowth and, following sciatic nerve injury, Twitcher axons were regeneration-competent, at a time point where axonopathy was already ongoing. Psychosine, the toxic substrate that accumulates in KD, induced lipid raft clustering. At the mechanistic level, TrkA recruitment to lipid rafts was dysregulated in Twitcher neurons, and defective activation of the ERK1/2 and AKT pathways was identified. Besides defective recruitment of signaling molecules to lipid rafts, the early steps of endocytosis and the transport of endocytic and synaptic vesicles were impaired in Twitcher DRG neurons. Defects in axonal transport, specifically in the retrograde component, correlated with decreased levels of dynein, abnormal levels of post-translational tubulin modifications and decreased microtubule stability. The identification of the axonal defects that precede demyelination in KD, together with the finding that Twitcher axons are regeneration-competent when axonopathy is already installed, opens new windows of action to effectively correct the neuropathology that characterizes this disorder.http://www.sciencedirect.com/science/article/pii/S0969996114000540Krabbe's diseaseTwitcherLeukodystrophyMyelinAxonal transportEndocytosis |
| spellingShingle | Carla Andreia Teixeira Catarina Oliveira Miranda Vera Filipe Sousa Telma Emanuela Santos Ana Rita Malheiro Melani Solomon Gustavo H. Maegawa Pedro Brites Mónica Mendes Sousa Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease Neurobiology of Disease Krabbe's disease Twitcher Leukodystrophy Myelin Axonal transport Endocytosis |
| title | Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease |
| title_full | Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease |
| title_fullStr | Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease |
| title_full_unstemmed | Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease |
| title_short | Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease |
| title_sort | early axonal loss accompanied by impaired endocytosis abnormal axonal transport and decreased microtubule stability occur in the model of krabbe s disease |
| topic | Krabbe's disease Twitcher Leukodystrophy Myelin Axonal transport Endocytosis |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114000540 |
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