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

Cell Rep. 2021 Oct 12;37(2):109831. doi: 10.1016/j.celrep.2021.109831.

Authors

Affiliations

¹ Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
² Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
³ Department of Neurology, University of Utah, Salt Lake City, UT 84112, USA.
⁴ Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 55455, USA.
⁶ RISS Bioinformatics, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.
⁷ Department of Neurology, University of Utah, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: stefan.pulst@hsc.utah.edu.
⁸ Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: orrxx002@umn.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Ataxin-1 / genetics
Ataxin-1 / metabolism
Atrophy
Behavior, Animal / drug effects
Calbindins / metabolism
Chemokines, CC / agonists*
Chemokines, CC / genetics
Chemokines, CC / metabolism
Cholecystokinin / genetics
Cholecystokinin / metabolism
Disease Models, Animal
Female
Genetic Predisposition to Disease
Guanine Nucleotide Exchange Factors / genetics
Guanine Nucleotide Exchange Factors / metabolism
Male
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Motor Activity / drug effects
Nerve Degeneration
Neuropeptides / genetics
Neuropeptides / metabolism
Purkinje Cells / drug effects*
Purkinje Cells / enzymology
Purkinje Cells / pathology
Signal Transduction
Spinocerebellar Ataxias / drug therapy*
Spinocerebellar Ataxias / enzymology
Spinocerebellar Ataxias / genetics
Spinocerebellar Ataxias / pathology
Tetragastrin / analogs & derivatives*
Tetragastrin / pharmacology

Substances

Ataxin-1
Atxn1 protein, mouse
Calbindins
Ccl28 protein, mouse
Chemokines, CC
Guanine Nucleotide Exchange Factors
Neuropeptides
Pcp2 protein, mouse
Tetragastrin
A 71623
Cholecystokinin
Mechanistic Target of Rapamycin Complex 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding