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

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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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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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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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