Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1

Stephanie L. Coffin; Mark A. Durham; Larissa Nitschke; Eder Xhako; Amanda M. Brown; Jean Pierre Revelli; Esmeralda Villavicencio Gonzalez; Tao Lin; Hillary Handler; Yanwan Dai; Alexander J. Trostle; Ying Wooi Wan; Zhandong Liu; Roy V. Sillitoe; Harry T. Orr; Huda Y. Zoghbi

doi:10.1016/j.neuron.2022.11.016

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1

Stephanie L. Coffin, Mark A. Durham, Larissa Nitschke, Eder Xhako, Amanda M. Brown, Jean Pierre Revelli, Esmeralda Villavicencio Gonzalez, Tao Lin, Hillary Handler, Yanwan Dai, Alexander J. Trostle, Ying Wooi Wan, Zhandong Liu, Roy V. Sillitoe, Harry T. Orr, Huda Y. Zoghbi

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

12 Scopus citations

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1^154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased proteomics, we identified three ATXN1-interacting transcription factors: RFX1, ZBTB5, and ZKSCAN1. We observed altered expression of RFX1 and ZKSCAN1 target genes in SCA1 mice and patient-derived iNeurons, highlighting their potential contributions to disease. Together, these data underscore the complexity of mechanisms driving cellular vulnerability in SCA1.

Original language	English (US)
Pages (from-to)	481-492.e8
Journal	Neuron
Volume	111
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2022.11.016
State	Published - Feb 15 2023

Bibliographical note

Funding Information:
We thank Sameer Bajikar, Jessica Butts, and Hamin Lee for critical comments on the manuscript and Won-Seok Lee and Carolyn Bondar for technical advice on histology and immunoprecipitations. We further thank the Baylor College of Medicine (BCM) Mass Spectrometry Proteomics Core, BCM Genetically Engineered Mouse Core, Jan and Dan Duncan Neurological Research Institute (NRI) Microscopy Core, NRI RNA In Situ Hybridization Core, and the NRI Animal Phenotyping & Preclinical Endpoints Core Facilities. Funding: This work was funded by the National Institute of Neurological Disorders and Stroke/NIH grant 1F31NS115296 (S.L.C.), the National Institute of Neurological Disorders and Stroke/NIH grant R37NS027699 (H.Y.Z.), JPB Foundation grant MR-2020-2156 (H.Y.Z.), the Howard Hughes Medical Institute (H.Y.Z.), CPRIT Core Facility Award RP170005 (BCM Mass Spectrometry Proteomics Core), P30 Cancer Center Support Grant NCICA125123 (BCM Mass Spectrometry Proteomics Core), S10 High End Instrument Award OD026804 (BCM Mass Spectrometry Proteomics Core), NIH grant P30CA125123 (BCM Genetically Engineered Mouse Core), the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH IDDRC grant U54 HD083092 (NRI RNA In Situ Hybridization core), and the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH grant P50HD103555 (NRI Microscopy Core, NRI Animal Phenotyping & Preclinical Endpoints Core Facilities). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
We thank Sameer Bajikar, Jessica Butts, and Hamin Lee for critical comments on the manuscript and Won-Seok Lee and Carolyn Bondar for technical advice on histology and immunoprecipitations. We further thank the Baylor College of Medicine (BCM) Mass Spectrometry Proteomics Core, BCM Genetically Engineered Mouse Core, Jan and Dan Duncan Neurological Research Institute (NRI) Microscopy Core, NRI RNA In Situ Hybridization Core, and the NRI Animal Phenotyping & Preclinical Endpoints Core Facilities. Funding: This work was funded by the National Institute of Neurological Disorders and Stroke/NIH grant 1F31NS115296 (S.L.C.), the National Institute of Neurological Disorders and Stroke/NIH grant R37NS027699 (H.Y.Z.), JPB Foundation grant MR-2020-2156 (H.Y.Z.), the Howard Hughes Medical Institute (H.Y.Z.), CPRIT Core Facility Award RP170005 (BCM Mass Spectrometry Proteomics Core), P30 Cancer Center Support Grant NCICA125123 (BCM Mass Spectrometry Proteomics Core), S10 High End Instrument Award OD026804 (BCM Mass Spectrometry Proteomics Core), NIH grant P30CA125123 (BCM Genetically Engineered Mouse Core), the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH IDDRC grant U54 HD083092 (NRI RNA In Situ Hybridization core), and the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH grant P50HD103555 (NRI Microscopy Core, NRI Animal Phenotyping & Preclinical Endpoints Core Facilities). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. S.L.C. and H.Y.Z. conceived the study, wrote, and edited the manuscript. S.L.C. L.N. M.A.D. H.P.H. R.V.S. H.T.O. and H.Y.Z. designed experiments and interpreted data. S.L.C. and L.N. designed CRISPR strategy and generated mouse models. S.L.C. E.X. J.-P.R. and E.V.G. performed molecular and behavioral assays. S.L.C. M.A.D. Y.D. A.J.T. Y.-W.W. and Z.L. performed RNA sequencing and analyzed the data. M.A.D. performed CUT&RUN experiment and analyzed the data. S.L.C. A.M.B. and T.L. performed histology assays. A.M.B. T.L. and R.V.S. planned and carried out electrophysiological experiments and analyses. All authors reviewed the manuscript and provided input. H.Y.Z. is a co-founder of Cajal Neuroscience and a member of its scientific advisory board. H.Y.Z. is a science partner at the Column Group and a board member of Regeneron. H.Y.Z. collaborates with UCB and Ionis Pharmaceuticals on projects not relevant to this publication.

Publisher Copyright:
© 2022 The Authors

Keywords

ATXN1
CIC
CUT&RUN
SCA1
neurodegeneration
polyglutamine expansion disorders
proteomics
regional vulnerability
spinocerebellar ataxia type 1
transcriptomics

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1016/j.neuron.2022.11.016

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Coffin, S. L., Durham, M. A., Nitschke, L., Xhako, E., Brown, A. M., Revelli, J. P., Villavicencio Gonzalez, E., Lin, T., Handler, H., Dai, Y., Trostle, A. J., Wan, Y. W., Liu, Z., Sillitoe, R. V., Orr, H. T., & Zoghbi, H. Y. (2023). Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1. Neuron, 111(4), 481-492.e8. https://doi.org/10.1016/j.neuron.2022.11.016

Coffin, SL, Durham, MA, Nitschke, L, Xhako, E, Brown, AM, Revelli, JP, Villavicencio Gonzalez, E, Lin, T, Handler, H, Dai, Y, Trostle, AJ, Wan, YW, Liu, Z, Sillitoe, RV, Orr, HT & Zoghbi, HY 2023, 'Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1', Neuron, vol. 111, no. 4, pp. 481-492.e8. https://doi.org/10.1016/j.neuron.2022.11.016

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title = "Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1",

abstract = "Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased proteomics, we identified three ATXN1-interacting transcription factors: RFX1, ZBTB5, and ZKSCAN1. We observed altered expression of RFX1 and ZKSCAN1 target genes in SCA1 mice and patient-derived iNeurons, highlighting their potential contributions to disease. Together, these data underscore the complexity of mechanisms driving cellular vulnerability in SCA1.",

keywords = "ATXN1, CIC, CUT&RUN, SCA1, neurodegeneration, polyglutamine expansion disorders, proteomics, regional vulnerability, spinocerebellar ataxia type 1, transcriptomics",

author = "Coffin, {Stephanie L.} and Durham, {Mark A.} and Larissa Nitschke and Eder Xhako and Brown, {Amanda M.} and Revelli, {Jean Pierre} and {Villavicencio Gonzalez}, Esmeralda and Tao Lin and Hillary Handler and Yanwan Dai and Trostle, {Alexander J.} and Wan, {Ying Wooi} and Zhandong Liu and Sillitoe, {Roy V.} and Orr, {Harry T.} and Zoghbi, {Huda Y.}",

note = "Funding Information: We thank Sameer Bajikar, Jessica Butts, and Hamin Lee for critical comments on the manuscript and Won-Seok Lee and Carolyn Bondar for technical advice on histology and immunoprecipitations. We further thank the Baylor College of Medicine (BCM) Mass Spectrometry Proteomics Core, BCM Genetically Engineered Mouse Core, Jan and Dan Duncan Neurological Research Institute (NRI) Microscopy Core, NRI RNA In Situ Hybridization Core, and the NRI Animal Phenotyping & Preclinical Endpoints Core Facilities. Funding: This work was funded by the National Institute of Neurological Disorders and Stroke/NIH grant 1F31NS115296 (S.L.C.), the National Institute of Neurological Disorders and Stroke/NIH grant R37NS027699 (H.Y.Z.), JPB Foundation grant MR-2020-2156 (H.Y.Z.), the Howard Hughes Medical Institute (H.Y.Z.), CPRIT Core Facility Award RP170005 (BCM Mass Spectrometry Proteomics Core), P30 Cancer Center Support Grant NCICA125123 (BCM Mass Spectrometry Proteomics Core), S10 High End Instrument Award OD026804 (BCM Mass Spectrometry Proteomics Core), NIH grant P30CA125123 (BCM Genetically Engineered Mouse Core), the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH IDDRC grant U54 HD083092 (NRI RNA In Situ Hybridization core), and the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH grant P50HD103555 (NRI Microscopy Core, NRI Animal Phenotyping & Preclinical Endpoints Core Facilities). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Sameer Bajikar, Jessica Butts, and Hamin Lee for critical comments on the manuscript and Won-Seok Lee and Carolyn Bondar for technical advice on histology and immunoprecipitations. We further thank the Baylor College of Medicine (BCM) Mass Spectrometry Proteomics Core, BCM Genetically Engineered Mouse Core, Jan and Dan Duncan Neurological Research Institute (NRI) Microscopy Core, NRI RNA In Situ Hybridization Core, and the NRI Animal Phenotyping & Preclinical Endpoints Core Facilities. Funding: This work was funded by the National Institute of Neurological Disorders and Stroke/NIH grant 1F31NS115296 (S.L.C.), the National Institute of Neurological Disorders and Stroke/NIH grant R37NS027699 (H.Y.Z.), JPB Foundation grant MR-2020-2156 (H.Y.Z.), the Howard Hughes Medical Institute (H.Y.Z.), CPRIT Core Facility Award RP170005 (BCM Mass Spectrometry Proteomics Core), P30 Cancer Center Support Grant NCICA125123 (BCM Mass Spectrometry Proteomics Core), S10 High End Instrument Award OD026804 (BCM Mass Spectrometry Proteomics Core), NIH grant P30CA125123 (BCM Genetically Engineered Mouse Core), the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH IDDRC grant U54 HD083092 (NRI RNA In Situ Hybridization core), and the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH grant P50HD103555 (NRI Microscopy Core, NRI Animal Phenotyping & Preclinical Endpoints Core Facilities). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. S.L.C. and H.Y.Z. conceived the study, wrote, and edited the manuscript. S.L.C. L.N. M.A.D. H.P.H. R.V.S. H.T.O. and H.Y.Z. designed experiments and interpreted data. S.L.C. and L.N. designed CRISPR strategy and generated mouse models. S.L.C. E.X. J.-P.R. and E.V.G. performed molecular and behavioral assays. S.L.C. M.A.D. Y.D. A.J.T. Y.-W.W. and Z.L. performed RNA sequencing and analyzed the data. M.A.D. performed CUT&RUN experiment and analyzed the data. S.L.C. A.M.B. and T.L. performed histology assays. A.M.B. T.L. and R.V.S. planned and carried out electrophysiological experiments and analyses. All authors reviewed the manuscript and provided input. H.Y.Z. is a co-founder of Cajal Neuroscience and a member of its scientific advisory board. H.Y.Z. is a science partner at the Column Group and a board member of Regeneron. H.Y.Z. collaborates with UCB and Ionis Pharmaceuticals on projects not relevant to this publication. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2023",

month = feb,

day = "15",

doi = "10.1016/j.neuron.2022.11.016",

language = "English (US)",

volume = "111",

pages = "481--492.e8",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "4",

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T1 - Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1

AU - Coffin, Stephanie L.

AU - Durham, Mark A.

AU - Nitschke, Larissa

AU - Xhako, Eder

AU - Brown, Amanda M.

AU - Revelli, Jean Pierre

AU - Villavicencio Gonzalez, Esmeralda

AU - Lin, Tao

AU - Handler, Hillary

AU - Dai, Yanwan

AU - Trostle, Alexander J.

AU - Wan, Ying Wooi

AU - Liu, Zhandong

AU - Sillitoe, Roy V.

AU - Orr, Harry T.

AU - Zoghbi, Huda Y.

N1 - Funding Information: We thank Sameer Bajikar, Jessica Butts, and Hamin Lee for critical comments on the manuscript and Won-Seok Lee and Carolyn Bondar for technical advice on histology and immunoprecipitations. We further thank the Baylor College of Medicine (BCM) Mass Spectrometry Proteomics Core, BCM Genetically Engineered Mouse Core, Jan and Dan Duncan Neurological Research Institute (NRI) Microscopy Core, NRI RNA In Situ Hybridization Core, and the NRI Animal Phenotyping & Preclinical Endpoints Core Facilities. Funding: This work was funded by the National Institute of Neurological Disorders and Stroke/NIH grant 1F31NS115296 (S.L.C.), the National Institute of Neurological Disorders and Stroke/NIH grant R37NS027699 (H.Y.Z.), JPB Foundation grant MR-2020-2156 (H.Y.Z.), the Howard Hughes Medical Institute (H.Y.Z.), CPRIT Core Facility Award RP170005 (BCM Mass Spectrometry Proteomics Core), P30 Cancer Center Support Grant NCICA125123 (BCM Mass Spectrometry Proteomics Core), S10 High End Instrument Award OD026804 (BCM Mass Spectrometry Proteomics Core), NIH grant P30CA125123 (BCM Genetically Engineered Mouse Core), the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH IDDRC grant U54 HD083092 (NRI RNA In Situ Hybridization core), and the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH grant P50HD103555 (NRI Microscopy Core, NRI Animal Phenotyping & Preclinical Endpoints Core Facilities). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Sameer Bajikar, Jessica Butts, and Hamin Lee for critical comments on the manuscript and Won-Seok Lee and Carolyn Bondar for technical advice on histology and immunoprecipitations. We further thank the Baylor College of Medicine (BCM) Mass Spectrometry Proteomics Core, BCM Genetically Engineered Mouse Core, Jan and Dan Duncan Neurological Research Institute (NRI) Microscopy Core, NRI RNA In Situ Hybridization Core, and the NRI Animal Phenotyping & Preclinical Endpoints Core Facilities. Funding: This work was funded by the National Institute of Neurological Disorders and Stroke/NIH grant 1F31NS115296 (S.L.C.), the National Institute of Neurological Disorders and Stroke/NIH grant R37NS027699 (H.Y.Z.), JPB Foundation grant MR-2020-2156 (H.Y.Z.), the Howard Hughes Medical Institute (H.Y.Z.), CPRIT Core Facility Award RP170005 (BCM Mass Spectrometry Proteomics Core), P30 Cancer Center Support Grant NCICA125123 (BCM Mass Spectrometry Proteomics Core), S10 High End Instrument Award OD026804 (BCM Mass Spectrometry Proteomics Core), NIH grant P30CA125123 (BCM Genetically Engineered Mouse Core), the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH IDDRC grant U54 HD083092 (NRI RNA In Situ Hybridization core), and the Eunice Kennedy Shriver National Institute of Child Health & Human Development NIH grant P50HD103555 (NRI Microscopy Core, NRI Animal Phenotyping & Preclinical Endpoints Core Facilities). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. S.L.C. and H.Y.Z. conceived the study, wrote, and edited the manuscript. S.L.C. L.N. M.A.D. H.P.H. R.V.S. H.T.O. and H.Y.Z. designed experiments and interpreted data. S.L.C. and L.N. designed CRISPR strategy and generated mouse models. S.L.C. E.X. J.-P.R. and E.V.G. performed molecular and behavioral assays. S.L.C. M.A.D. Y.D. A.J.T. Y.-W.W. and Z.L. performed RNA sequencing and analyzed the data. M.A.D. performed CUT&RUN experiment and analyzed the data. S.L.C. A.M.B. and T.L. performed histology assays. A.M.B. T.L. and R.V.S. planned and carried out electrophysiological experiments and analyses. All authors reviewed the manuscript and provided input. H.Y.Z. is a co-founder of Cajal Neuroscience and a member of its scientific advisory board. H.Y.Z. is a science partner at the Column Group and a board member of Regeneron. H.Y.Z. collaborates with UCB and Ionis Pharmaceuticals on projects not relevant to this publication. Publisher Copyright: © 2022 The Authors

PY - 2023/2/15

Y1 - 2023/2/15

N2 - Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased proteomics, we identified three ATXN1-interacting transcription factors: RFX1, ZBTB5, and ZKSCAN1. We observed altered expression of RFX1 and ZKSCAN1 target genes in SCA1 mice and patient-derived iNeurons, highlighting their potential contributions to disease. Together, these data underscore the complexity of mechanisms driving cellular vulnerability in SCA1.

AB - Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased proteomics, we identified three ATXN1-interacting transcription factors: RFX1, ZBTB5, and ZKSCAN1. We observed altered expression of RFX1 and ZKSCAN1 target genes in SCA1 mice and patient-derived iNeurons, highlighting their potential contributions to disease. Together, these data underscore the complexity of mechanisms driving cellular vulnerability in SCA1.

KW - ATXN1

KW - CIC

KW - CUT&RUN

KW - SCA1

KW - neurodegeneration

KW - polyglutamine expansion disorders

KW - proteomics

KW - regional vulnerability

KW - spinocerebellar ataxia type 1

KW - transcriptomics

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DO - 10.1016/j.neuron.2022.11.016

M3 - Article

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VL - 111

SP - 481-492.e8

JO - Neuron

JF - Neuron

IS - 4

ER -

Disruption of the ATXN1-CIC complex reveals the role of additional nuclear ATXN1 interactors in spinocerebellar ataxia type 1

Abstract

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Keywords

PubMed: MeSH publication types

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