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Our preliminary study revealed that its absence caused progressive spastic ataxia, accompanied by the loss of Purkinje cells in mice. Here, we generated <jats:italic>Ankfy1<\/jats:italic>-floxed (<jats:italic>Ankfy1<\/jats:italic>\n            <jats:sup>f\/f<\/jats:sup>) mice, in which conditional inactivation of the\u00a0<jats:italic>Ankfy1<\/jats:italic>\u00a0gene was achieved specifically in cerebellar Purkinje cells via crossing with a transgenic mouse strain expressing Cre recombinase under the regulatory control of the Purkinje cell protein 2 (PCP2) promoter. We employed data-independent acquisition (DIA) mass spectrometry to compare the protein expression profiles in cerebellar samples. The samples were obtained from two groups of male mice. The first group consisted of three Pcp2-Cre; <jats:italic>Ankfy1<\/jats:italic>\n            <jats:sup>f\/f<\/jats:sup> male mice, where the <jats:italic>Ankfy1<\/jats:italic> gene was conditionally knocked out in Purkinje cells, and these mice were designated as the conditional knockout (CKO) group. The second group included three Cre-negative; <jats:italic>Ankfy1<\/jats:italic>\n            <jats:sup>f\/f<\/jats:sup> littermate male mice served as the wild-type (WT) control group. The results identified 69 (45 upregulated and 24 downregulated) differentially expressed proteins (DEPs) in CKO vs. WT male mice with a 1.5-fold change. Enrichment analyses of these DEPs based on the Gene Ontology (GO), Orthologous Groups of Proteins (COG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases revealed functional clusters associated with neuronal cell morphogenesis, extracellular structures, regulation of Rho-GTPase, calcium signaling pathway, etc. <jats:italic>Itgb2<\/jats:italic>, which was upregulated in CKO mice, was the top hub gene according to protein\u2013protein interaction (PPI) analysis. We selected seven interesting differentially expressed genes (<jats:italic>Arhgdib<\/jats:italic>, <jats:italic>Impa2<\/jats:italic>, <jats:italic>Pcp2<\/jats:italic>, <jats:italic>Pcp4<\/jats:italic>, <jats:italic>Ppp1r17<\/jats:italic>, <jats:italic>Rhobtb2<\/jats:italic>, and <jats:italic>Cdc123<\/jats:italic>) for further validation. <jats:italic>Arhgdib<\/jats:italic> and <jats:italic>Imp2a<\/jats:italic> expression was increased in the cerebellum of CKO male and female mice, and <jats:italic>Pcp2<\/jats:italic> and <jats:italic>Pcp4<\/jats:italic> expression was decreased. Western blotting and immunofluorescence verified the upregulation of ARHGDIB and the downregulation of PCP2 in the cerebellum. Our proteomic analysis of conditional <jats:italic>Ankfy1<\/jats:italic> knockout mice may guide future research to help develop treatments for progressive spastic ataxia.<\/jats:p>","DOI":"10.1038\/s41598-025-06398-8","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T14:59:08Z","timestamp":1751381948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of spastic ataxia-related proteins via comparative proteomic analysis of the cerebellum of conditional Ankfy1 knockout mice"],"prefix":"10.1038","volume":"15","author":[{"given":"Rong","family":"Fu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linlin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rumeng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuneng","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"6398_CR1","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1212\/WNL.0b013e31826d5fb0","volume":"79","author":"ST de Bot","year":"2012","unstructured":"de Bot, S. T., Willemsen, M. A., Vermeer, S., Kremer, H. P. & van de Warrenburg, B. P. Reviewing the genetic causes of spastic-ataxias. Neurology 79, 1507\u20131514. https:\/\/doi.org\/10.1212\/WNL.0b013e31826d5fb0 (2012).","journal-title":"Neurology"},{"key":"6398_CR2","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1007\/s12311-021-01345-5","volume":"21","author":"JL Pedroso","year":"2022","unstructured":"Pedroso, J. L. et al. A diagnostic approach to spastic ataxia syndromes. Cerebellum 21, 1073\u20131084. https:\/\/doi.org\/10.1007\/s12311-021-01345-5 (2022).","journal-title":"Cerebellum"},{"key":"6398_CR3","doi-asserted-by":"publisher","unstructured":"Ito, K. et al. Molecular cloning of a novel 130-kDa cytoplasmic protein, Ankhzn, containing Ankyrin repeats hooked to a zinc finger motif. Biochem. Biophys. Res. 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