Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice

Emily A.L. Wozniak; Zhao Chen; Sharan Paul; Praseuth Yang; Karla P. Figueroa; Jill Friedrich; Tyler Tschumperlin; Michael Berken; Melissa Ingram; Christine Henzler; Stefan M. Pulst; Harry T. Orr

doi:10.1016/j.celrep.2021.109831

Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice

Emily A.L. Wozniak, Zhao Chen, Sharan Paul, Praseuth Yang, Karla P. Figueroa, Jill Friedrich, Tyler Tschumperlin, Michael Berken, Melissa Ingram, Christine Henzler, Stefan M. Pulst, Harry T. Orr

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

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Abstract

Spinocerebellar ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identify cerebellar upregulation of the peptide hormone cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. Administration of a Cck1R agonist, A71623, to Pcp2-ATXN1[30Q]D776;Cck^−/− and Pcp2-AXTN1[82Q] mice dampens Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improves motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Moreover, the Cck1R agonist A71623 corrects mTORC1 signaling and improves expression of calbindin in cerebella of AXTN1[82Q] and ATXN2[127Q] mice. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.

Original language	English (US)
Article number	109831
Journal	Cell reports
Volume	37
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.109831
State	Published - Oct 12 2021

Bibliographical note

Funding Information:
This study was supported by NIH/NINDS grant RO1NS 045667 (H.T.O.) and NIH/NINDS grants R37NS033123, R21NSNS103009, and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony. E.A.L.W. Z.C. and S.P. contributed equally to this work. E.A.L.W. Z.C. S.P. K.P.F. S.M.P. and H.T.O. contributed to the conception and design of the study. E.A.L.W. Z.C. P.Y. J.F. T.T. and M.B. contributed to tissue selection, collection, and analyses. E.A.L.W. and M.I. performed RNA extractions for RNA-seq. M.I. and C.H. performed RNA-seq expression and WGCNA bioinformatics analyses. C.H. supervised bioinformatics analyses. M.I. E.A.L.W. Z.C. S.P. P.Y. C.H. S.M.P. and H.T.O. interpreted the data and prepared the manuscript. E.A.L.W. and H.T.O. declare patent US 10,973,812 B2 (issued April 13, 2021) as relevant to the work in this paper. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.

Funding Information:
This study was supported by NIH / NINDS grant RO1NS 045667 (H.T.O.) and NIH / NINDS grants R37NS033123 , R21NSNS103009 , and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony.

Publisher Copyright:
© 2021

Keywords

Purkinje cells
cholecystokinin
mTORC1 signaling
neuroprotection
spinocerebellar ataxia

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10.1016/j.celrep.2021.109831

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Wozniak, E. A. L., Chen, Z., Paul, S., Yang, P., Figueroa, K. P., Friedrich, J., Tschumperlin, T., Berken, M., Ingram, M., Henzler, C., Pulst, S. M., & Orr, H. T. (2021). Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice. Cell reports, 37(2), Article 109831. https://doi.org/10.1016/j.celrep.2021.109831

@article{27f747033f5a4622a937c55c900b6c97,

title = "Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice",

abstract = "Spinocerebellar ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identify cerebellar upregulation of the peptide hormone cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. Administration of a Cck1R agonist, A71623, to Pcp2-ATXN1[30Q]D776;Cck−/− and Pcp2-AXTN1[82Q] mice dampens Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improves motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Moreover, the Cck1R agonist A71623 corrects mTORC1 signaling and improves expression of calbindin in cerebella of AXTN1[82Q] and ATXN2[127Q] mice. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.",

keywords = "Purkinje cells, cholecystokinin, mTORC1 signaling, neuroprotection, spinocerebellar ataxia",

author = "Wozniak, {Emily A.L.} and Zhao Chen and Sharan Paul and Praseuth Yang and Figueroa, {Karla P.} and Jill Friedrich and Tyler Tschumperlin and Michael Berken and Melissa Ingram and Christine Henzler and Pulst, {Stefan M.} and Orr, {Harry T.}",

note = "Funding Information: This study was supported by NIH/NINDS grant RO1NS 045667 (H.T.O.) and NIH/NINDS grants R37NS033123, R21NSNS103009, and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony. E.A.L.W. Z.C. and S.P. contributed equally to this work. E.A.L.W. Z.C. S.P. K.P.F. S.M.P. and H.T.O. contributed to the conception and design of the study. E.A.L.W. Z.C. P.Y. J.F. T.T. and M.B. contributed to tissue selection, collection, and analyses. E.A.L.W. and M.I. performed RNA extractions for RNA-seq. M.I. and C.H. performed RNA-seq expression and WGCNA bioinformatics analyses. C.H. supervised bioinformatics analyses. M.I. E.A.L.W. Z.C. S.P. P.Y. C.H. S.M.P. and H.T.O. interpreted the data and prepared the manuscript. E.A.L.W. and H.T.O. declare patent US 10,973,812 B2 (issued April 13, 2021) as relevant to the work in this paper. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: This study was supported by NIH / NINDS grant RO1NS 045667 (H.T.O.) and NIH / NINDS grants R37NS033123 , R21NSNS103009 , and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony. Publisher Copyright: {\textcopyright} 2021",

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doi = "10.1016/j.celrep.2021.109831",

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T1 - Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice

AU - Wozniak, Emily A.L.

AU - Chen, Zhao

AU - Paul, Sharan

AU - Yang, Praseuth

AU - Figueroa, Karla P.

AU - Friedrich, Jill

AU - Tschumperlin, Tyler

AU - Berken, Michael

AU - Ingram, Melissa

AU - Henzler, Christine

AU - Pulst, Stefan M.

AU - Orr, Harry T.

N1 - Funding Information: This study was supported by NIH/NINDS grant RO1NS 045667 (H.T.O.) and NIH/NINDS grants R37NS033123, R21NSNS103009, and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony. E.A.L.W. Z.C. and S.P. contributed equally to this work. E.A.L.W. Z.C. S.P. K.P.F. S.M.P. and H.T.O. contributed to the conception and design of the study. E.A.L.W. Z.C. P.Y. J.F. T.T. and M.B. contributed to tissue selection, collection, and analyses. E.A.L.W. and M.I. performed RNA extractions for RNA-seq. M.I. and C.H. performed RNA-seq expression and WGCNA bioinformatics analyses. C.H. supervised bioinformatics analyses. M.I. E.A.L.W. Z.C. S.P. P.Y. C.H. S.M.P. and H.T.O. interpreted the data and prepared the manuscript. E.A.L.W. and H.T.O. declare patent US 10,973,812 B2 (issued April 13, 2021) as relevant to the work in this paper. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: This study was supported by NIH / NINDS grant RO1NS 045667 (H.T.O.) and NIH / NINDS grants R37NS033123 , R21NSNS103009 , and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony. Publisher Copyright: © 2021

PY - 2021/10/12

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N2 - Spinocerebellar ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identify cerebellar upregulation of the peptide hormone cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. Administration of a Cck1R agonist, A71623, to Pcp2-ATXN1[30Q]D776;Cck−/− and Pcp2-AXTN1[82Q] mice dampens Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improves motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Moreover, the Cck1R agonist A71623 corrects mTORC1 signaling and improves expression of calbindin in cerebella of AXTN1[82Q] and ATXN2[127Q] mice. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.

AB - Spinocerebellar ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identify cerebellar upregulation of the peptide hormone cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. Administration of a Cck1R agonist, A71623, to Pcp2-ATXN1[30Q]D776;Cck−/− and Pcp2-AXTN1[82Q] mice dampens Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improves motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Moreover, the Cck1R agonist A71623 corrects mTORC1 signaling and improves expression of calbindin in cerebella of AXTN1[82Q] and ATXN2[127Q] mice. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.

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KW - mTORC1 signaling

KW - neuroprotection

KW - spinocerebellar ataxia

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Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice

Abstract

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