PT  - JOURNAL ARTICLE
AU  - Emily A.L. Wozniak
AU  - Zhao Chen
AU  - Sharan Paul
AU  - Praseuth Yang
AU  - Karla P. Figueroa
AU  - Jill Friedrich
AU  - Tyler Tschumperlin
AU  - Michael Berken
AU  - Melissa Ingram
AU  - Christine Henzler
AU  - Stefan M. Pulst
AU  - Harry T. Orr
TI  - Cholecystokinin 1 Receptor (Cck1R) Normalizes mTORC1 signaling and is Protective to Purkinje cells of SCA Mice
AID  - 10.1101/2021.02.16.431490
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.16.431490
4099  - http://biorxiv.org/content/early/2021/03/23/2021.02.16.431490.short
4100  - http://biorxiv.org/content/early/2021/03/23/2021.02.16.431490.full
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 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.Competing Interest StatementThe authors have declared no competing interest.