Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model

Using single-stranded adeno-associated virus serotype 9 (ssAAV9) vectors containing the neuron-specific synapsin-I promoter, we examined whether different administration routes (direct cerebellar cortical (DC), intrathecal (IT) and intravenous (IV) injections) could elicit specific transduction prof...

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Main Authors: Fathul Huda, Ayumu Konno, Yasunori Matsuzaki, Hanna Goenawan, Koichi Miyake, Takashi Shimada, Hirokazu Hirai
Format: Article
Language:English
Published: Elsevier 2014-01-01
Series:Molecular Therapy: Methods & Clinical Development
Online Access:http://www.sciencedirect.com/science/article/pii/S2329050116300997
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spelling doaj-71f2ab5a535048c686824279ffac405e2020-11-24T23:47:23ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012014-01-011C10.1038/mtm.2014.32Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse modelFathul Huda0Ayumu Konno1Yasunori Matsuzaki2Hanna Goenawan3Koichi Miyake4Takashi Shimada5Hirokazu Hirai6Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, JapanUsing single-stranded adeno-associated virus serotype 9 (ssAAV9) vectors containing the neuron-specific synapsin-I promoter, we examined whether different administration routes (direct cerebellar cortical (DC), intrathecal (IT) and intravenous (IV) injections) could elicit specific transduction profiles in the CNS. The DC injection route robustly and exclusively transduced the whole cerebellum, whereas the IT injection route primarily transduced the cerebellar lobules 9 and 10 close to the injection site and the spinal cord. An IV injection in neonatal mice weakly and homogenously transduced broad CNS areas. In the cerebellar cortex, the DC and IT injection routes transduced all neuron types, whereas the IV injection route primarily transduced Purkinje cells. To verify the usefulness of this method, we generated a mouse model of spinocerebellar ataxia type 1 (SCA1). Mice that received a DC injection of the ssAAV9 vector expressing mutant ATXN1, a protein responsible for SCA1, showed the intranuclear aggregation of mutant ATXN1 in Purkinje cells, significant atrophy of the Purkinje cell dendrites and progressive motor deficits, which are characteristics of SCA1. Thus, ssAAV9-mediated transduction areas, levels, and cell types change depending on the route of injection. Moreover, this approach can be used for the generation of different mouse models of CNS/neurodegenerative diseases.http://www.sciencedirect.com/science/article/pii/S2329050116300997
collection DOAJ
language English
format Article
sources DOAJ
author Fathul Huda
Ayumu Konno
Yasunori Matsuzaki
Hanna Goenawan
Koichi Miyake
Takashi Shimada
Hirokazu Hirai
spellingShingle Fathul Huda
Ayumu Konno
Yasunori Matsuzaki
Hanna Goenawan
Koichi Miyake
Takashi Shimada
Hirokazu Hirai
Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model
Molecular Therapy: Methods & Clinical Development
author_facet Fathul Huda
Ayumu Konno
Yasunori Matsuzaki
Hanna Goenawan
Koichi Miyake
Takashi Shimada
Hirokazu Hirai
author_sort Fathul Huda
title Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model
title_short Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model
title_full Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model
title_fullStr Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model
title_full_unstemmed Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model
title_sort distinct transduction profiles in the cns via three injection routes of aav9 and the application to generation of a neurodegenerative mouse model
publisher Elsevier
series Molecular Therapy: Methods & Clinical Development
issn 2329-0501
publishDate 2014-01-01
description Using single-stranded adeno-associated virus serotype 9 (ssAAV9) vectors containing the neuron-specific synapsin-I promoter, we examined whether different administration routes (direct cerebellar cortical (DC), intrathecal (IT) and intravenous (IV) injections) could elicit specific transduction profiles in the CNS. The DC injection route robustly and exclusively transduced the whole cerebellum, whereas the IT injection route primarily transduced the cerebellar lobules 9 and 10 close to the injection site and the spinal cord. An IV injection in neonatal mice weakly and homogenously transduced broad CNS areas. In the cerebellar cortex, the DC and IT injection routes transduced all neuron types, whereas the IV injection route primarily transduced Purkinje cells. To verify the usefulness of this method, we generated a mouse model of spinocerebellar ataxia type 1 (SCA1). Mice that received a DC injection of the ssAAV9 vector expressing mutant ATXN1, a protein responsible for SCA1, showed the intranuclear aggregation of mutant ATXN1 in Purkinje cells, significant atrophy of the Purkinje cell dendrites and progressive motor deficits, which are characteristics of SCA1. Thus, ssAAV9-mediated transduction areas, levels, and cell types change depending on the route of injection. Moreover, this approach can be used for the generation of different mouse models of CNS/neurodegenerative diseases.
url http://www.sciencedirect.com/science/article/pii/S2329050116300997
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