Cholecystokinin 1 Receptor (Cck1R) Activates mTORC1 signaling and is Protective to Purkinje cells in SCA Mice

Spinocerebellar Ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often incerebellar Purkinje neurons. Mouse models of SCA Type 1 (SCA1) have been used to study molecular mechanisms underlying Purkinje neuron degeneration and death. One 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. These results indicate that manipulation of the Cck-Cck1R pathway is a potential therapeutic target for treatment of diseases involving Purkinje neuron degeneration.