A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice

Veronica F. Colomer Gould; Daniel Goti; Donna Pearce; Guillermo A. Gonzalez; Hong Gao; Mario Bermudez de Leon; Nancy A. Jenkins; Neal G. Copeland; Christopher A. Ross; Dale R. Brown

doi:10.1016/j.nbd.2007.06.005

A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice

Veronica F. Colomer Gould
, Daniel Goti
, Donna Pearce
, Guillermo A. Gonzalez
, Hong Gao
, Mario Bermudez de Leon
, Nancy A. Jenkins
, Neal G. Copeland
, Christopher A. Ross
, Dale R. Brown

Research output: Contribution to journal › Article › peer-review

47 Citations (Scopus)

Abstract

Machado-Joseph disease also called spinocerebellar ataxia type 3 (MJD/SCA3) is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a polyglutamine expansion (mutant ataxin-3). Neuronal loss in MJD/SCA3 is associated with a mutant ataxin-3 toxic fragment. Defining mutant ataxin-3 proteolytic site(s) could facilitate the identification of the corresponding enzyme(s). Previously, we reported a mutant ataxin-3 mjd1a fragment in the brain of transgenic mice (Q71) that contained epitopes C-terminal to amino acid 220. In this study, we generated and characterized neuroblastoma cells and transgenic mice expressing mutant ataxin-3 mjd1a lacking amino acids 190-220 (deltaQ71). Less deltaQ71 than Q71 fragments were detected in the cell but not mouse model. The transgenic mice developed an MJD/SCA3-like phenotype and their brain homogenates had a fragment containing epitopes C-terminal to amino acid 220. Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190.

Original language	English
Pages (from-to)	362-369
Number of pages	8
Journal	Neurobiology of Disease
Volume	27
Issue number	3
DOIs	https://doi.org/10.1016/j.nbd.2007.06.005
Publication status	Published - 1 Sept 2007
Externally published	Yes

Bibliographical note

Funding Information:
We especially thank: (a) Debbie Swing for performing the zygote injections; (b) Mrs. Mary Keyser and Suzanne Fowble for budget administration; and (c) Dr. Pamela Talalay for critical editing of the manuscript. This work was supported by: (a) Donation from JCG (VCG); (b) NIH grant NS42731-01 (VCG); (c) AHA grant EIG 0140166N (VCG); and in part by (d) NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (NAJ, NGC).

Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.

All Science Journal Classification (ASJC) codes

Neurology

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10.1016/j.nbd.2007.06.005

https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=34548329581&origin=inward

Cite this

Colomer Gould, V. F., Goti, D., Pearce, D., Gonzalez, G. A., Gao, H., Bermudez de Leon, M., Jenkins, N. A., Copeland, N. G., Ross, C. A., & Brown, D. R. (2007). A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiology of Disease, 27(3), 362-369. https://doi.org/10.1016/j.nbd.2007.06.005

@article{bc398e75c502469a92087f109a88184c,

title = "A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice",

abstract = "Machado-Joseph disease also called spinocerebellar ataxia type 3 (MJD/SCA3) is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a polyglutamine expansion (mutant ataxin-3). Neuronal loss in MJD/SCA3 is associated with a mutant ataxin-3 toxic fragment. Defining mutant ataxin-3 proteolytic site(s) could facilitate the identification of the corresponding enzyme(s). Previously, we reported a mutant ataxin-3 mjd1a fragment in the brain of transgenic mice (Q71) that contained epitopes C-terminal to amino acid 220. In this study, we generated and characterized neuroblastoma cells and transgenic mice expressing mutant ataxin-3 mjd1a lacking amino acids 190-220 (deltaQ71). Less deltaQ71 than Q71 fragments were detected in the cell but not mouse model. The transgenic mice developed an MJD/SCA3-like phenotype and their brain homogenates had a fragment containing epitopes C-terminal to amino acid 220. Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190.",

author = "\{Colomer Gould\}, \{Veronica F.\} and Daniel Goti and Donna Pearce and Gonzalez, \{Guillermo A.\} and Hong Gao and \{Bermudez de Leon\}, Mario and Jenkins, \{Nancy A.\} and Copeland, \{Neal G.\} and Ross, \{Christopher A.\} and Brown, \{Dale R.\}",

note = "Funding Information: We especially thank: (a) Debbie Swing for performing the zygote injections; (b) Mrs. Mary Keyser and Suzanne Fowble for budget administration; and (c) Dr. Pamela Talalay for critical editing of the manuscript. This work was supported by: (a) Donation from JCG (VCG); (b) NIH grant NS42731-01 (VCG); (c) AHA grant EIG 0140166N (VCG); and in part by (d) NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (NAJ, NGC). Copyright: Copyright 2008 Elsevier B.V., All rights reserved.",

year = "2007",

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doi = "10.1016/j.nbd.2007.06.005",

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Colomer Gould, VF, Goti, D, Pearce, D, Gonzalez, GA, Gao, H, Bermudez de Leon, M, Jenkins, NA, Copeland, NG, Ross, CA & Brown, DR 2007, 'A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice', Neurobiology of Disease, vol. 27, no. 3, pp. 362-369. https://doi.org/10.1016/j.nbd.2007.06.005

TY - JOUR

T1 - A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice

AU - Colomer Gould, Veronica F.

AU - Goti, Daniel

AU - Pearce, Donna

AU - Gonzalez, Guillermo A.

AU - Gao, Hong

AU - Bermudez de Leon, Mario

AU - Jenkins, Nancy A.

AU - Copeland, Neal G.

AU - Ross, Christopher A.

AU - Brown, Dale R.

N1 - Funding Information: We especially thank: (a) Debbie Swing for performing the zygote injections; (b) Mrs. Mary Keyser and Suzanne Fowble for budget administration; and (c) Dr. Pamela Talalay for critical editing of the manuscript. This work was supported by: (a) Donation from JCG (VCG); (b) NIH grant NS42731-01 (VCG); (c) AHA grant EIG 0140166N (VCG); and in part by (d) NIH Intramural Research Program, National Cancer Institute, Center for Cancer Research (NAJ, NGC). Copyright: Copyright 2008 Elsevier B.V., All rights reserved.

PY - 2007/9/1

Y1 - 2007/9/1

N2 - Machado-Joseph disease also called spinocerebellar ataxia type 3 (MJD/SCA3) is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a polyglutamine expansion (mutant ataxin-3). Neuronal loss in MJD/SCA3 is associated with a mutant ataxin-3 toxic fragment. Defining mutant ataxin-3 proteolytic site(s) could facilitate the identification of the corresponding enzyme(s). Previously, we reported a mutant ataxin-3 mjd1a fragment in the brain of transgenic mice (Q71) that contained epitopes C-terminal to amino acid 220. In this study, we generated and characterized neuroblastoma cells and transgenic mice expressing mutant ataxin-3 mjd1a lacking amino acids 190-220 (deltaQ71). Less deltaQ71 than Q71 fragments were detected in the cell but not mouse model. The transgenic mice developed an MJD/SCA3-like phenotype and their brain homogenates had a fragment containing epitopes C-terminal to amino acid 220. Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190.

AB - Machado-Joseph disease also called spinocerebellar ataxia type 3 (MJD/SCA3) is a hereditary and neurodegenerative movement disorder caused by ataxin-3 with a polyglutamine expansion (mutant ataxin-3). Neuronal loss in MJD/SCA3 is associated with a mutant ataxin-3 toxic fragment. Defining mutant ataxin-3 proteolytic site(s) could facilitate the identification of the corresponding enzyme(s). Previously, we reported a mutant ataxin-3 mjd1a fragment in the brain of transgenic mice (Q71) that contained epitopes C-terminal to amino acid 220. In this study, we generated and characterized neuroblastoma cells and transgenic mice expressing mutant ataxin-3 mjd1a lacking amino acids 190-220 (deltaQ71). Less deltaQ71 than Q71 fragments were detected in the cell but not mouse model. The transgenic mice developed an MJD/SCA3-like phenotype and their brain homogenates had a fragment containing epitopes C-terminal to amino acid 220. Our results support the toxic fragment hypothesis and narrow the mutant ataxin-3 cleavage site to the N-terminus of amino acid 190.

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SN - 0969-9961

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JO - Neurobiology of Disease

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A Mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice

Abstract

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