Neuronal α-Synucleinopathy with Severe Movement Disorder in Mice Expressing A53T Human α-Synuclein
α-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore t...
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| Veröffentlicht in: | Neuron (Cambridge, Mass.) Mass.), 2002-05, Vol.34 (4), p.521-533 |
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| creator | Giasson, Benoit I. Duda, John E. Quinn, Shawn M. Zhang, Bin Trojanowski, John Q. Lee, Virginia M.-Y. |
| description | α-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human α-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, α-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal α-synuclein inclusions paralleling disease onset, and the α-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the α-synuclein inclusions contained 10–16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T α-synuclein leads to the formation of toxic filamentous α-synuclein neuronal inclusions that cause neurodegeneration. |
| doi_str_mv | 10.1016/S0896-6273(02)00682-7 |
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Although mounting evidence suggests that α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human α-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, α-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal α-synuclein inclusions paralleling disease onset, and the α-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the α-synuclein inclusions contained 10–16 nm wide fibrils similar to human pathological inclusions. 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Although mounting evidence suggests that α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human α-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, α-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal α-synuclein inclusions paralleling disease onset, and the α-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the α-synuclein inclusions contained 10–16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T α-synuclein leads to the formation of toxic filamentous α-synuclein neuronal inclusions that cause neurodegeneration.</description><subject>alpha-Synuclein</subject><subject>Animals</subject><subject>Axons - metabolism</subject><subject>Axons - pathology</subject><subject>Axons - ultrastructure</subject><subject>Behavior, Animal - physiology</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain - ultrastructure</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gene Expression Regulation - physiology</subject><subject>Humans</subject><subject>Inclusion Bodies - metabolism</subject><subject>Inclusion Bodies - pathology</subject><subject>Inclusion Bodies - ultrastructure</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microscopy, Electron</subject><subject>Movement Disorders - genetics</subject><subject>Movement Disorders - metabolism</subject><subject>Movement Disorders - pathology</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Nerve Tissue Proteins - ultrastructure</subject><subject>Neurodegenerative Diseases - genetics</subject><subject>Neurodegenerative Diseases - metabolism</subject><subject>Neurodegenerative Diseases - pathology</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neurons - ultrastructure</subject><subject>Phenotype</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Recombinant Fusion Proteins - ultrastructure</subject><subject>Solubility</subject><subject>Spinal Cord - metabolism</subject><subject>Spinal Cord - pathology</subject><subject>Spinal Cord - ultrastructure</subject><subject>Synucleins</subject><subject>Wallerian Degeneration - genetics</subject><subject>Wallerian Degeneration - metabolism</subject><subject>Wallerian Degeneration - pathology</subject><issn>0896-6273</issn><issn>1097-4199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMtOwzAQRS0EoqXwCSCvECwCtvNwskJVKRSphUXL2nKcCTVKnGInhX4WP8I3kT4EYsVqNmfunTkInVJyRQmNrqckTiIvYty_IOySkChmHt9DXUoS7gU0SfZR9wfpoCPnXgmhQZjQQ9ShjESM-LyLskdobGVkgb8-venKNKoAbaqFrOcr_K7rOZ7CEizgSbWEEkyNb7WrbAYWa4MnWgEefiwsOKfNC-6H_gyPmlKaP3HH6CCXhYOT3eyh57vhbDDyxk_3D4P-2FNBQmsvVyxVLJOU5BzSQCZEKggDFUd5e3cWyTQEJv04S5UMuWQBoxJCooI051HsS7-Hzre5C1u9NeBqUWqnoCikgapxgsYB45TTFgy3oLKVcxZysbC6lHYlKBFrvWKjV6zdCcLERq_g7d7ZrqBJS8h-t3Y-W-BmC0D75lKDFU5pMAoybUHVIqv0PxXfka-M5w</recordid><startdate>20020516</startdate><enddate>20020516</enddate><creator>Giasson, Benoit I.</creator><creator>Duda, John E.</creator><creator>Quinn, Shawn M.</creator><creator>Zhang, Bin</creator><creator>Trojanowski, John Q.</creator><creator>Lee, Virginia M.-Y.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20020516</creationdate><title>Neuronal α-Synucleinopathy with Severe Movement Disorder in Mice Expressing A53T Human α-Synuclein</title><author>Giasson, Benoit I. ; Duda, John E. ; Quinn, Shawn M. ; Zhang, Bin ; Trojanowski, John Q. ; Lee, Virginia M.-Y.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-fc2bc2da10f7eb4a90ace54c86f459d6ab5e2a38dbca57a2421ae50c4bf7683a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>alpha-Synuclein</topic><topic>Animals</topic><topic>Axons - metabolism</topic><topic>Axons - pathology</topic><topic>Axons - ultrastructure</topic><topic>Behavior, Animal - physiology</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Brain - ultrastructure</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Gene Expression Regulation - physiology</topic><topic>Humans</topic><topic>Inclusion Bodies - metabolism</topic><topic>Inclusion Bodies - pathology</topic><topic>Inclusion Bodies - ultrastructure</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microscopy, Electron</topic><topic>Movement Disorders - genetics</topic><topic>Movement Disorders - metabolism</topic><topic>Movement Disorders - pathology</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Nerve Tissue Proteins - ultrastructure</topic><topic>Neurodegenerative Diseases - genetics</topic><topic>Neurodegenerative Diseases - metabolism</topic><topic>Neurodegenerative Diseases - pathology</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neurons - ultrastructure</topic><topic>Phenotype</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Recombinant Fusion Proteins - ultrastructure</topic><topic>Solubility</topic><topic>Spinal Cord - metabolism</topic><topic>Spinal Cord - pathology</topic><topic>Spinal Cord - ultrastructure</topic><topic>Synucleins</topic><topic>Wallerian Degeneration - genetics</topic><topic>Wallerian Degeneration - metabolism</topic><topic>Wallerian Degeneration - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Giasson, Benoit I.</creatorcontrib><creatorcontrib>Duda, John E.</creatorcontrib><creatorcontrib>Quinn, Shawn M.</creatorcontrib><creatorcontrib>Zhang, Bin</creatorcontrib><creatorcontrib>Trojanowski, John Q.</creatorcontrib><creatorcontrib>Lee, Virginia M.-Y.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Giasson, Benoit I.</au><au>Duda, John E.</au><au>Quinn, Shawn M.</au><au>Zhang, Bin</au><au>Trojanowski, John Q.</au><au>Lee, Virginia M.-Y.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neuronal α-Synucleinopathy with Severe Movement Disorder in Mice Expressing A53T Human α-Synuclein</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><addtitle>Neuron</addtitle><date>2002-05-16</date><risdate>2002</risdate><volume>34</volume><issue>4</issue><spage>521</spage><epage>533</epage><pages>521-533</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><abstract>α-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that α-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human α-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, α-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal α-synuclein inclusions paralleling disease onset, and the α-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the α-synuclein inclusions contained 10–16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T α-synuclein leads to the formation of toxic filamentous α-synuclein neuronal inclusions that cause neurodegeneration.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>12062037</pmid><doi>10.1016/S0896-6273(02)00682-7</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | alpha-Synuclein Animals Axons - metabolism Axons - pathology Axons - ultrastructure Behavior, Animal - physiology Brain - metabolism Brain - pathology Brain - ultrastructure Disease Models, Animal Female Gene Expression Regulation - physiology Humans Inclusion Bodies - metabolism Inclusion Bodies - pathology Inclusion Bodies - ultrastructure Male Mice Mice, Transgenic Microscopy, Electron Movement Disorders - genetics Movement Disorders - metabolism Movement Disorders - pathology Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Nerve Tissue Proteins - ultrastructure Neurodegenerative Diseases - genetics Neurodegenerative Diseases - metabolism Neurodegenerative Diseases - pathology Neurons - metabolism Neurons - pathology Neurons - ultrastructure Phenotype Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Recombinant Fusion Proteins - ultrastructure Solubility Spinal Cord - metabolism Spinal Cord - pathology Spinal Cord - ultrastructure Synucleins Wallerian Degeneration - genetics Wallerian Degeneration - metabolism Wallerian Degeneration - pathology |
| title | Neuronal α-Synucleinopathy with Severe Movement Disorder in Mice Expressing A53T Human α-Synuclein |
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