Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice
Superoxide dismutase 1 (SOD1), a ubiquitously expressed enzyme, detoxifies superoxide radicals and participates in copper homeostasis. Mutations in this enzyme have been linked to a subset of autosomal dominant cases of familial amyotrophic lateral sclerosis (FALS), a disorder characterized by selec...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
1998-07-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996198901784 |
| id |
doaj-a84e546c32874331bb3496288a06ce73 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
David R. Borchelt Philip C. Wong Mark W. Becher Carlos A. Pardo Michael K. Lee Zuo-Shang Xu Gopal Thinakaran Nancy A. Jenkins Neal G. Copeland Sangram S. Sisodia Don W. Cleveland Donald L. Price Paul N. Hoffman |
| spellingShingle |
David R. Borchelt Philip C. Wong Mark W. Becher Carlos A. Pardo Michael K. Lee Zuo-Shang Xu Gopal Thinakaran Nancy A. Jenkins Neal G. Copeland Sangram S. Sisodia Don W. Cleveland Donald L. Price Paul N. Hoffman Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice Neurobiology of Disease axonal transport superoxide dismutase 1 slow componentb familial amyotrophic lateral sclerosis mutant. |
| author_facet |
David R. Borchelt Philip C. Wong Mark W. Becher Carlos A. Pardo Michael K. Lee Zuo-Shang Xu Gopal Thinakaran Nancy A. Jenkins Neal G. Copeland Sangram S. Sisodia Don W. Cleveland Donald L. Price Paul N. Hoffman |
| author_sort |
David R. Borchelt |
| title |
Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice |
| title_short |
Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice |
| title_full |
Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice |
| title_fullStr |
Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice |
| title_full_unstemmed |
Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice |
| title_sort |
axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice |
| publisher |
Elsevier |
| series |
Neurobiology of Disease |
| issn |
1095-953X |
| publishDate |
1998-07-01 |
| description |
Superoxide dismutase 1 (SOD1), a ubiquitously expressed enzyme, detoxifies superoxide radicals and participates in copper homeostasis. Mutations in this enzyme have been linked to a subset of autosomal dominant cases of familial amyotrophic lateral sclerosis (FALS), a disorder characterized by selective degeneration of motor neurons. Transgenic mice expressing FALS mutant human (Hu) SOD1 at high levels develop a motor neuron disease, indicating that mutant Hu SOD1 gains properties that are particularly toxic to motor neurons. In this report, we demonstrate that transgenic mice expressing Hu SOD1 with the G37R FALS mutation, but not mice expressing wild-type enzyme, develop focal increases in immunoreactivity in the proximal axons of spinal motor neurons. This SOD1 immunoreactivity and immunoreactivity to hypophosphorylated neurofilament H epitopes are found adjacent to small vacuoles in axons. Using metabolic radiolabeling methods, we show that mutant G37R HuSOD1 as well as endogenous mouse SOD1 are transported anterograde in slow componentbin motor and sensory axons of the sciatic nerve. Together, these findings suggest that anterogradely transported mutant SOD1 may act locally to damage motor axons. |
| topic |
axonal transport superoxide dismutase 1 slow componentb familial amyotrophic lateral sclerosis mutant. |
| url |
http://www.sciencedirect.com/science/article/pii/S0969996198901784 |
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doaj-a84e546c32874331bb3496288a06ce732021-03-20T05:00:18ZengElsevierNeurobiology of Disease1095-953X1998-07-01512735Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic MiceDavid R. Borchelt0Philip C. Wong1Mark W. Becher2Carlos A. Pardo3Michael K. Lee4Zuo-Shang Xu5Gopal Thinakaran6Nancy A. Jenkins7Neal G. Copeland8Sangram S. Sisodia9Don W. Cleveland10Donald L. Price11Paul N. Hoffman12Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Ophthalmology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21205; Worchester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545; The Mammalian Genetics Laboratory, The National Cancer Institute, Frederick, Maryland; Department of Medicine, Department of Neuroscience, Ludwig Institute, University of California, San Diego, La Jolla, California, 92093Superoxide dismutase 1 (SOD1), a ubiquitously expressed enzyme, detoxifies superoxide radicals and participates in copper homeostasis. Mutations in this enzyme have been linked to a subset of autosomal dominant cases of familial amyotrophic lateral sclerosis (FALS), a disorder characterized by selective degeneration of motor neurons. Transgenic mice expressing FALS mutant human (Hu) SOD1 at high levels develop a motor neuron disease, indicating that mutant Hu SOD1 gains properties that are particularly toxic to motor neurons. In this report, we demonstrate that transgenic mice expressing Hu SOD1 with the G37R FALS mutation, but not mice expressing wild-type enzyme, develop focal increases in immunoreactivity in the proximal axons of spinal motor neurons. This SOD1 immunoreactivity and immunoreactivity to hypophosphorylated neurofilament H epitopes are found adjacent to small vacuoles in axons. Using metabolic radiolabeling methods, we show that mutant G37R HuSOD1 as well as endogenous mouse SOD1 are transported anterograde in slow componentbin motor and sensory axons of the sciatic nerve. Together, these findings suggest that anterogradely transported mutant SOD1 may act locally to damage motor axons.http://www.sciencedirect.com/science/article/pii/S0969996198901784axonal transportsuperoxide dismutase 1slow componentbfamilial amyotrophic lateral sclerosismutant. |