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.
Bibliographical noteFunding Information:
This study was supported by NIH/NINDS grant RO1NS 045667 (H.T.O.) and NIH/NINDS grants R37NS033123, R21NSNS103009, and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony. E.A.L.W. Z.C. and S.P. contributed equally to this work. E.A.L.W. Z.C. S.P. K.P.F. S.M.P. and H.T.O. contributed to the conception and design of the study. E.A.L.W. Z.C. P.Y. J.F. T.T. and M.B. contributed to tissue selection, collection, and analyses. E.A.L.W. and M.I. performed RNA extractions for RNA-seq. M.I. and C.H. performed RNA-seq expression and WGCNA bioinformatics analyses. C.H. supervised bioinformatics analyses. M.I. E.A.L.W. Z.C. S.P. P.Y. C.H. S.M.P. and H.T.O. interpreted the data and prepared the manuscript. 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. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.
This study was supported by NIH / NINDS grant RO1NS 045667 (H.T.O.) and NIH / NINDS grants R37NS033123 , R21NSNS103009 , and UO1NS103883 (S.M.P.). The authors thank the Biomedical Genomics Center, Mouse Phenotyping Core at the University of Minnesota and Orion Rainwater for propagating and maintaining the mouse colony.
- Purkinje cells
- mTORC1 signaling
- spinocerebellar ataxia