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Cholecystokinin 1 Receptor (Cck1R) 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 identified cerebellar up-regulation 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. A Cck1R agonist, A71623 administered to Pcp2-ATXN1[30Q]D776;Cck-/- and Pcp2-AXTN1[82Q] mice dampened Purkinje neuron pathology and associated deficits in motor performance. In addition, A71623 administration improved motor performance of Pcp2-ATXN2[127Q] SCA2 mice. Moreover, the Cck1R agonist A71623 corrected mTORC1 signaling and improved 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE180969 | GEO | 2022/01/11

REPOSITORIES: GEO

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Cholecystokinin 1 Receptor (Cck1R) Activation Restores Normal mTORC1 signaling and is Protective to Purkinje cells of SCA Mice

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