Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.
Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FA...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3680447?pdf=render |
| _version_ | 1819326989570408448 |
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| author | Gerardo A Morfini Daryl A Bosco Hannah Brown Rodolfo Gatto Agnieszka Kaminska Yuyu Song Linda Molla Lisa Baker M Natalia Marangoni Sarah Berth Ehsan Tavassoli Carolina Bagnato Ashutosh Tiwari Lawrence J Hayward Gustavo F Pigino D Martin Watterson Chun-Fang Huang Gary Banker Robert H Brown Scott T Brady |
| author_facet | Gerardo A Morfini Daryl A Bosco Hannah Brown Rodolfo Gatto Agnieszka Kaminska Yuyu Song Linda Molla Lisa Baker M Natalia Marangoni Sarah Berth Ehsan Tavassoli Carolina Bagnato Ashutosh Tiwari Lawrence J Hayward Gustavo F Pigino D Martin Watterson Chun-Fang Huang Gary Banker Robert H Brown Scott T Brady |
| author_sort | Gerardo A Morfini |
| collection | DOAJ |
| description | Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS. |
| first_indexed | 2024-12-24T13:03:43Z |
| format | Article |
| id | doaj.art-c19ff8f0c04447fd912d1b2f9f9ca560 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-24T13:03:43Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c19ff8f0c04447fd912d1b2f9f9ca5602022-12-21T16:54:05ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6523510.1371/journal.pone.0065235Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.Gerardo A MorfiniDaryl A BoscoHannah BrownRodolfo GattoAgnieszka KaminskaYuyu SongLinda MollaLisa BakerM Natalia MarangoniSarah BerthEhsan TavassoliCarolina BagnatoAshutosh TiwariLawrence J HaywardGustavo F PiginoD Martin WattersonChun-Fang HuangGary BankerRobert H BrownScott T BradyDying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.http://europepmc.org/articles/PMC3680447?pdf=render |
| spellingShingle | Gerardo A Morfini Daryl A Bosco Hannah Brown Rodolfo Gatto Agnieszka Kaminska Yuyu Song Linda Molla Lisa Baker M Natalia Marangoni Sarah Berth Ehsan Tavassoli Carolina Bagnato Ashutosh Tiwari Lawrence J Hayward Gustavo F Pigino D Martin Watterson Chun-Fang Huang Gary Banker Robert H Brown Scott T Brady Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS ONE |
| title | Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. |
| title_full | Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. |
| title_fullStr | Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. |
| title_full_unstemmed | Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. |
| title_short | Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. |
| title_sort | inhibition of fast axonal transport by pathogenic sod1 involves activation of p38 map kinase |
| url | http://europepmc.org/articles/PMC3680447?pdf=render |
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