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Cholecystokinin 1 receptor activation restores normal mTORC1 signaling and is protective to Purkinje cells of SCA mice.
- Source :
-
Cell reports [Cell Rep] 2021 Oct 12; Vol. 37 (2), pp. 109831. - Publication Year :
- 2021
-
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 <superscript>-/-</superscript> 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.<br />Competing Interests: Declaration of interests 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.<br /> (Copyright © 2021. Published by Elsevier Inc.)
- Subjects :
- Animals
Ataxin-1 genetics
Ataxin-1 metabolism
Atrophy
Behavior, Animal drug effects
Calbindins metabolism
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
Mice, Inbred C57BL
Mice, Knockout
Motor Activity drug effects
Nerve Degeneration
Neuropeptides genetics
Neuropeptides metabolism
Purkinje Cells enzymology
Purkinje Cells pathology
Signal Transduction
Spinocerebellar Ataxias enzymology
Spinocerebellar Ataxias genetics
Spinocerebellar Ataxias pathology
Tetragastrin pharmacology
Mice
Chemokines, CC agonists
Mechanistic Target of Rapamycin Complex 1 metabolism
Purkinje Cells drug effects
Spinocerebellar Ataxias drug therapy
Tetragastrin analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 37
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 34644575
- Full Text :
- https://doi.org/10.1016/j.celrep.2021.109831