A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration

Kei Watase; Edwin J. Weeber; Bisong Xu; Barbara Antalffy; Lisa Yuva-Paylor; Kouichi Hashimoto; Masanobu Kano; Richard Atkinson; Yaling Sun; Dawna L. Armstrong; J. David Sweatt; Harry T. Orr; Richard Paylor; Huda Y. Zoghbi

doi:10.1016/S0896-6273(02)00733-X

A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration

Kei Watase
, Edwin J. Weeber
, Bisong Xu
, Barbara Antalffy
, Lisa Yuva-Paylor
, Kouichi Hashimoto
, Masanobu Kano
, Richard Atkinson
, Yaling Sun
, Dawna L. Armstrong
, J. David Sweatt
, Harry T. Orr
, Richard Paylor
, Huda Y. Zoghbi

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

303 Scopus citations

Abstract

To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse we targeted 154 CAG repeats into the endogenous mouse locus. Sca1^154Q/2Q mice developed a progressive neurological disorder that resembles human SCA1 featuring motor incoordination cognitive deficits wasting and premature death accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells the most affected in SCA1 did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.

Original language	English (US)
Pages (from-to)	905-919
Number of pages	15
Journal	Neuron
Volume	34
Issue number	6
DOIs	https://doi.org/10.1016/S0896-6273(02)00733-X
State	Published - Jun 13 2002

Bibliographical note

Funding Information:
We thank Dr. Hannes Vogel and Michael Fernandez for expert technical assistance and V. Brandt for a critical reading of the manuscript. This work is supported by grants from the National Institute of Neurological Disorders and Stroke of the NIH to H.Y.Z. (NS27699) and H.T.O. (NS22920) and by cores from the Mental Retardation Research Center at Baylor College of Medicine. H.Y.Z. is an Investigator and K.W. is a Postdoctoral Research Associate with the Howard Hughes Medical Institute.

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Watase, K., Weeber, E. J., Xu, B., Antalffy, B., Yuva-Paylor, L., Hashimoto, K., Kano, M., Atkinson, R., Sun, Y., Armstrong, D. L., Sweatt, J. D., Orr, H. T., Paylor, R., & Zoghbi, H. Y. (2002). A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron, 34(6), 905-919. https://doi.org/10.1016/S0896-6273(02)00733-X

Watase, K, Weeber, EJ, Xu, B, Antalffy, B, Yuva-Paylor, L, Hashimoto, K, Kano, M, Atkinson, R, Sun, Y, Armstrong, DL, Sweatt, JD, Orr, HT, Paylor, R & Zoghbi, HY 2002, 'A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration', Neuron, vol. 34, no. 6, pp. 905-919. https://doi.org/10.1016/S0896-6273(02)00733-X

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title = "A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration",

abstract = "To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse we targeted 154 CAG repeats into the endogenous mouse locus. Sca1154Q/2Q mice developed a progressive neurological disorder that resembles human SCA1 featuring motor incoordination cognitive deficits wasting and premature death accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells the most affected in SCA1 did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.",

author = "Kei Watase and Weeber, \{Edwin J.\} and Bisong Xu and Barbara Antalffy and Lisa Yuva-Paylor and Kouichi Hashimoto and Masanobu Kano and Richard Atkinson and Yaling Sun and Armstrong, \{Dawna L.\} and Sweatt, \{J. David\} and Orr, \{Harry T.\} and Richard Paylor and Zoghbi, \{Huda Y.\}",

note = "Funding Information: We thank Dr. Hannes Vogel and Michael Fernandez for expert technical assistance and V. Brandt for a critical reading of the manuscript. This work is supported by grants from the National Institute of Neurological Disorders and Stroke of the NIH to H.Y.Z. (NS27699) and H.T.O. (NS22920) and by cores from the Mental Retardation Research Center at Baylor College of Medicine. H.Y.Z. is an Investigator and K.W. is a Postdoctoral Research Associate with the Howard Hughes Medical Institute.",

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doi = "10.1016/S0896-6273(02)00733-X",

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AU - Watase, Kei

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AU - Xu, Bisong

AU - Antalffy, Barbara

AU - Yuva-Paylor, Lisa

AU - Hashimoto, Kouichi

AU - Kano, Masanobu

AU - Atkinson, Richard

AU - Sun, Yaling

AU - Armstrong, Dawna L.

AU - Sweatt, J. David

AU - Orr, Harry T.

AU - Paylor, Richard

AU - Zoghbi, Huda Y.

N1 - Funding Information: We thank Dr. Hannes Vogel and Michael Fernandez for expert technical assistance and V. Brandt for a critical reading of the manuscript. This work is supported by grants from the National Institute of Neurological Disorders and Stroke of the NIH to H.Y.Z. (NS27699) and H.T.O. (NS22920) and by cores from the Mental Retardation Research Center at Baylor College of Medicine. H.Y.Z. is an Investigator and K.W. is a Postdoctoral Research Associate with the Howard Hughes Medical Institute.

PY - 2002/6/13

Y1 - 2002/6/13

N2 - To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse we targeted 154 CAG repeats into the endogenous mouse locus. Sca1154Q/2Q mice developed a progressive neurological disorder that resembles human SCA1 featuring motor incoordination cognitive deficits wasting and premature death accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells the most affected in SCA1 did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.

AB - To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse we targeted 154 CAG repeats into the endogenous mouse locus. Sca1154Q/2Q mice developed a progressive neurological disorder that resembles human SCA1 featuring motor incoordination cognitive deficits wasting and premature death accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells the most affected in SCA1 did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.

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A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration

Abstract

Bibliographical note

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