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.
Subject(s)
Chemokines, CC/agonists , Mechanistic Target of Rapamycin Complex 1/metabolism , Purkinje Cells/drug effects , Spinocerebellar Ataxias/drug therapy , Tetragastrin/analogs & derivatives , 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/pharmacologyABSTRACT
SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression in ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice.
