{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:39:36Z","timestamp":1764333576408,"version":"build-2065373602"},"reference-count":114,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG AU96\/21-1"],"award-info":[{"award-number":["DFG AU96\/21-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>The Ataxin-2-like (ATXN2L) protein is required to survive embryonic development, as documented in mice with the constitutive absence of the ATXN2L Lsm, LsmAD, and PAM2 domains due to knock-out (KO) of exons 5\u20138 with a frameshift. Its less abundant paralog, Ataxin-2 (ATXN2), has an extended N-terminus, where a polyglutamine domain is prone to expansions, mediating vulnerability to the polygenic adult motor neuron disease ALS (Amyotrophic Lateral Sclerosis) or causing the monogenic neurodegenerative processes of Spinocerebellar Ataxia Type 2 (SCA2), depending on larger mutation sizes. Here, we elucidated the physiological function of ATXN2L by deleting the LsmAD and PAM2 motifs via loxP-mediated KO of exons 10\u201317 with a frameshift. Crossing heterozygous floxed mice with constitutive Cre-deleter animals confirmed embryonic lethality among offspring. Crossing with CamK2a-CreERT2 mice and injecting tamoxifen for conditional deletion achieved chimeric ATXN2L absence in CamK2a-positive frontal cortex neurons and reduced spontaneous horizontal movement. Global proteome profiling of frontal cortex homogenate showed ATXN2L levels decreased to 75% and dysregulations enriched in the alternative splicing pathway. Nuclear proteins with Sm domains are critical to performing splicing; therefore, our data suggest that the Like-Sm (Lsm, LsmAD) domains in ATXN2L serve a role in splice regulation, despite their perinuclear location.<\/jats:p>","DOI":"10.3390\/cells14191532","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T14:16:29Z","timestamp":1759241789000},"page":"1532","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Conditional ATXN2L-Null in Adult Frontal Cortex CamK2a+ Neurons Does Not Cause Cell Death but Restricts Spontaneous Mobility and Affects the Alternative Splicing Pathway"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3208-1805","authenticated-orcid":false,"given":"Jana","family":"Key","sequence":"first","affiliation":[{"name":"Clinic of Neurology, Experimental Neurology, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0887-2359","authenticated-orcid":false,"given":"Luis-Enrique","family":"Almaguer-Mederos","sequence":"additional","affiliation":[{"name":"Clinic of Neurology, Experimental Neurology, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arvind Reddy","family":"Kandi","sequence":"additional","affiliation":[{"name":"Clinic of Neurology, Experimental Neurology, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9138-5542","authenticated-orcid":false,"given":"Meike","family":"Fellenz","sequence":"additional","affiliation":[{"name":"Institute for Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Fachbereich Medizin, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzana","family":"Gispert","sequence":"additional","affiliation":[{"name":"Clinic of Neurology, Experimental Neurology, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"K\u00f6pf","sequence":"additional","affiliation":[{"name":"Clinic of Neurology, Experimental Neurology, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0170-868X","authenticated-orcid":false,"given":"David","family":"Meierhofer","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Molecular Genetics, Ihnestra\u00dfe 63-73, 14195 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3931-2947","authenticated-orcid":false,"given":"Thomas","family":"Deller","sequence":"additional","affiliation":[{"name":"Institute for Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Fachbereich Medizin, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Auburger","sequence":"additional","affiliation":[{"name":"Clinic of Neurology, Experimental Neurology, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Str. 7, 60528 Frankfurt am Main, Germany"},{"name":"Institute for Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Fachbereich Medizin, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1073\/pnas.071033998","article-title":"The Sm domain is an ancient RNA-binding motif with oligo(U) specificity","volume":"98","author":"Achsel","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/35006676","article-title":"Yeast Sm-like proteins function in mRNA decapping and decay","volume":"404","author":"Tharun","year":"2000","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"636","DOI":"10.4161\/rna.24538","article-title":"Archaeal and eukaryotic homologs of Hfq: A structural and evolutionary perspective on Sm function","volume":"10","author":"Mura","year":"2013","journal-title":"RNA Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Swisher, K.D., and Parker, R. (2010). Localization to, and effects of Pbp1, Pbp4, Lsm12, Dhh1, and Pab1 on stress granules in Saccharomyces cerevisiae. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010006"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1021\/acs.jproteome.6b00647","article-title":"Quantitative Global Proteomics of Yeast PBP1 Deletion Mutants and Their Stress Responses Identifies Glucose Metabolism, Mitochondrial, and Stress Granule Changes","volume":"16","author":"Seidel","year":"2017","journal-title":"J. Proteome Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.cell.2019.02.043","article-title":"Yeast Ataxin-2 Forms an Intracellular Condensate Required for the Inhibition of TORC1 Signaling during Respiratory Growth","volume":"177","author":"Yang","year":"2019","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.cell.2019.02.044","article-title":"Redox State Controls Phase Separation of the Yeast Ataxin-2 Protein via Reversible Oxidation of Its Methionine-Rich Low-Complexity Domain","volume":"177","author":"Kato","year":"2019","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1385\/JMN:15:3:231","article-title":"The ortholog of human ataxin-2 is essential for early embryonic patterning in C. elegans","volume":"15","author":"Kiehl","year":"2000","journal-title":"J. Mol. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.1242\/dev.01352","article-title":"ATX-2, the C. elegans ortholog of ataxin 2, functions in translational regulation in the germline","volume":"131","author":"Ciosk","year":"2004","journal-title":"Development"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E4620","DOI":"10.1073\/pnas.1512156113","article-title":"Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor","volume":"113","author":"Bar","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Stubenvoll, M.D., Medley, J.C., Irwin, M., and Song, M.H. (2016). ATX-2, the C. elegans Ortholog of Human Ataxin-2, Regulates Centrosome Size and Microtubule Dynamics. PLoS Genet., 12.","DOI":"10.1101\/076604"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/tra.12647","article-title":"Conserved role for Ataxin-2 in mediating endoplasmic reticulum dynamics","volume":"20","author":"Gnazzo","year":"2019","journal-title":"Traffic"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"RP97812","DOI":"10.7554\/eLife.97812","article-title":"Katanin, kinesin-13, and ataxin-2 inhibit premature interaction between maternal and paternal genomes in C. elegans zygotes","volume":"13","author":"Beath","year":"2024","journal-title":"Elife"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1093\/genetics\/162.4.1687","article-title":"A Drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation","volume":"162","author":"Satterfield","year":"2002","journal-title":"Genetics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1093\/hmg\/ddl173","article-title":"Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes","volume":"15","author":"Satterfield","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Al-Ramahi, I., Perez, A.M., Lim, J., Zhang, M., Sorensen, R., de Haro, M., Branco, J., Pulst, S.M., Zoghbi, H.Y., and Botas, J. (2007). dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030234"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E655","DOI":"10.1073\/pnas.1107198108","article-title":"The Ataxin-2 protein is required for microRNA function and synapse-specific long-term olfactory habituation","volume":"108","author":"McCann","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1126\/science.1234785","article-title":"ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila","volume":"340","author":"Lim","year":"2013","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1126\/science.1234746","article-title":"A role for Drosophila ATX2 in activation of PER translation and circadian behavior","volume":"340","author":"Zhang","year":"2013","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E99","DOI":"10.1073\/pnas.1309543111","article-title":"FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control","volume":"111","author":"Sudhakaran","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1002\/2211-5463.12124","article-title":"Drosophila ataxin-2 gene encodes two differentially expressed isoforms and its function in larval fat body is crucial for development of peripheral tissues","volume":"6","author":"Vianna","year":"2016","journal-title":"FEBS Open Bio"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.molcel.2017.03.004","article-title":"LSM12 and ME31B\/DDX6 Define Distinct Modes of Posttranscriptional Regulation by ATAXIN-2 Protein Complex in Drosophila Circadian Pacemaker Neurons","volume":"66","author":"Lee","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.neuron.2018.04.032","article-title":"RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration","volume":"98","author":"Bakthavachalu","year":"2018","journal-title":"Neuron"},{"key":"ref_24","first-page":"870","article-title":"Ataxin-2 Dysregulation Triggers a Compensatory Fragile X Mental Retardation Protein Decrease in Drosophila C4da Neurons","volume":"43","author":"Cha","year":"2020","journal-title":"Mol. Cells"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e60326","DOI":"10.7554\/eLife.60326","article-title":"Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation","volume":"10","author":"Singh","year":"2021","journal-title":"Elife"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103536","DOI":"10.1016\/j.isci.2021.103536","article-title":"Ataxin-2 is essential for cytoskeletal dynamics and neurodevelopment in Drosophila","volume":"25","author":"Norkett","year":"2022","journal-title":"iScience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"jkac100","DOI":"10.1093\/g3journal\/jkac100","article-title":"The Nab2 RNA-binding protein patterns dendritic and axonal projections through a planar cell polarity-sensitive mechanism","volume":"12","author":"Corgiat","year":"2022","journal-title":"G3"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Petrauskas, A., Fortunati, D.L., Kandi, A.R., Pothapragada, S.S., Agrawal, K., Singh, A., Huelsmeier, J., Hillebrand, J., Brown, G., and Chaturvedi, D. (2024). Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation. PLoS Genet., 20.","DOI":"10.1371\/journal.pgen.1011251"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.tins.2017.06.004","article-title":"Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2","volume":"40","author":"Auburger","year":"2017","journal-title":"Trends Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Jimenez-Lopez, D., and Guzman, P. (2014). Insights into the evolution and domain structure of Ataxin-2 proteins across eukaryotes. BMC Res. Notes, 7.","DOI":"10.1186\/1756-0500-7-453"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/ng1196-269","article-title":"Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2","volume":"14","author":"Pulst","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/ng1196-277","article-title":"Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT","volume":"14","author":"Sanpei","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/ng1196-285","article-title":"Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG\/glutamine repeats","volume":"14","author":"Imbert","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/ana.20220","article-title":"Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia 2","volume":"56","author":"Seifried","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1007\/s00702-005-0287-3","article-title":"Spinocerebellar ataxias types 2 and 3: Degeneration of the pre-cerebellar nuclei isolates the three phylogenetically defined regions of the cerebellum","volume":"112","author":"Rub","year":"2005","journal-title":"J. Neural Transm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s00401-005-1014-8","article-title":"Involvement of the cranial nerves and their nuclei in spinocerebellar ataxia type 2 (SCA2)","volume":"109","author":"Gierga","year":"2005","journal-title":"Acta Neuropathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1093\/hmg\/ddi321","article-title":"Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways","volume":"14","author":"Ralser","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1212\/01.wnl.0000247054.90322.14","article-title":"Stages of sleep pathology in spinocerebellar ataxia type 2 (SCA2)","volume":"67","author":"Tuin","year":"2006","journal-title":"Neurology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1093\/hmg\/ddn035","article-title":"Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice","volume":"17","author":"Brodesser","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12311-008-0019-y","article-title":"Spinocerebellar ataxia 2 (SCA2)","volume":"7","author":"Rub","year":"2008","journal-title":"Cerebellum"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1016\/j.cellsig.2008.05.018","article-title":"Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking","volume":"20","author":"Nonis","year":"2008","journal-title":"Cell. Signal"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1093\/brain\/awg234","article-title":"Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance","volume":"126","author":"Rub","year":"2003","journal-title":"Brain"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.expneurol.2008.09.020","article-title":"Ataxin-2 associates with rough endoplasmic reticulum","volume":"215","author":"Eich","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1399-0004.2009.01358.x","article-title":"Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis","volume":"78","author":"Falcon","year":"2010","journal-title":"Clin. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/B978-0-444-51892-7.00026-7","article-title":"Spinocerebellar ataxia type 2","volume":"103","author":"Auburger","year":"2012","journal-title":"Handb. Clin. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.pneurobio.2013.01.001","article-title":"Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7","volume":"104","author":"Rub","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.1093\/brain\/awv255","article-title":"No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra","volume":"138","author":"Schols","year":"2015","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1074\/mcp.M115.056770","article-title":"Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations","volume":"15","author":"Meierhofer","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s12311-016-0762-4","article-title":"Atxn2 Knockout and CAG42-Knock-in Cerebellum Shows Similarly Dysregulated Expression in Calcium Homeostasis Pathway","volume":"16","author":"Halbach","year":"2017","journal-title":"Cerebellum"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bbadis.2016.05.017","article-title":"Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K\/mTOR and is induced by starvation","volume":"1862","author":"Nonis","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/bpa.12412","article-title":"On the distribution of intranuclear and cytoplasmic aggregates in the brainstem of patients with spinocerebellar ataxia type 2 and 3","volume":"27","author":"Seidel","year":"2017","journal-title":"Brain Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sen, N.E., Canet-Pons, J., Halbach, M.V., Arsovic, A., Pilatus, U., Chae, W.H., Kaya, Z.E., Seidel, K., Rollmann, E., and Mittelbronn, M. (2019). Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation. Neurobiol. Dis., 132.","DOI":"10.1016\/j.nbd.2019.104559"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Xu, F., Kula-Eversole, E., Iwanaszko, M., Lim, C., and Allada, R. (2019). Ataxin2 functions via CrebA to mediate Huntingtin toxicity in circadian clock neurons. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008356"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nature09320","article-title":"Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS","volume":"466","author":"Elden","year":"2010","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nature22038","article-title":"Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice","volume":"544","author":"Becker","year":"2017","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.nbd.2011.08.021","article-title":"The modulation of Amyotrophic Lateral Sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect","volume":"45","author":"Gispert","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Lahut, S., Omur, O., Uyan, O., Agim, Z.S., Ozoguz, A., Parman, Y., Deymeer, F., Oflazer, P., Koc, F., and Ozcelik, H. (2012). ATXN2 and its neighbouring gene SH2B3 are associated with increased ALS risk in the Turkish population. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042956"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1093\/hmg\/ddr045","article-title":"Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients","volume":"20","author":"Lee","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jmb.2004.11.024","article-title":"An integrative approach to gain insights into the cellular function of human ataxin-2","volume":"346","author":"Ralser","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1091\/mbc.e06-12-1120","article-title":"Ataxin-2 interacts with the DEAD\/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules","volume":"18","author":"Nonhoff","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Damrath, E., Heck, M.V., Gispert, S., Azizov, M., Nowock, J., Seifried, C., Rub, U., Walter, M., and Auburger, G. (2012). ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002920"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Kaehler, C., Isensee, J., Nonhoff, U., Terrey, M., Hucho, T., Lehrach, H., and Krobitsch, S. (2012). Ataxin-2-like is a regulator of stress granules and processing bodies. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050134"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.molcel.2014.05.022","article-title":"Direct binding of Ataxin-2 to distinct elements in 3\u2032 UTRs promotes mRNA stability and protein expression","volume":"55","author":"Yokoshi","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10048-015-0441-5","article-title":"Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate","volume":"16","author":"Fittschen","year":"2015","journal-title":"Neurogenetics"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"15810","DOI":"10.1074\/jbc.RA120.013835","article-title":"Direct evidence that Ataxin-2 is a translational activator mediating cytoplasmic polyadenylation","volume":"295","author":"Inagaki","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Canet-Pons, J., Sen, N.E., Arsovic, A., Almaguer-Mederos, L.E., Halbach, M.V., Key, J., Doring, C., Kerksiek, A., Picchiarelli, G., and Cassel, R. (2021). Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression. Neurobiol. Dis., 152.","DOI":"10.1016\/j.nbd.2021.105289"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1016\/j.molcel.2023.05.025","article-title":"Poly(A)-binding protein is an ataxin-2 chaperone that regulates biomolecular condensates","volume":"83","author":"Boeynaems","year":"2023","journal-title":"Mol. Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3245","DOI":"10.1016\/j.cell.2023.05.045","article-title":"Circadian clocks are modulated by compartmentalized oscillating translation","volume":"186","author":"Zhuang","year":"2023","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Wang, J.Y., Liu, Y.J., Zhang, X.L., Liu, Y.H., Jiang, L.L., and Hu, H.Y. (2024). PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.107413"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zhang, S., Zhang, Y., Chen, T., Hu, H.Y., and Lu, C. (2025). The LSmAD Domain of Ataxin-2 Modulates the Structure and RNA Binding of Its Preceding LSm Domain. Cells, 14.","DOI":"10.3390\/cells14050383"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s12031-012-9949-4","article-title":"Ataxin-2 modulates the levels of Grb2 and SRC but not ras signaling","volume":"51","author":"Drost","year":"2013","journal-title":"J. Mol. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"9139","DOI":"10.1074\/jbc.M105970200","article-title":"Cloning and characterization of a family of proteins associated with Mpl","volume":"277","author":"Meunier","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.cell.2005.07.012","article-title":"General translational repression by activators of mRNA decapping","volume":"122","author":"Coller","year":"2005","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1261\/rna.075812.120","article-title":"Pdc2\/Pat1 increases the range of decay factors and RNA bound by the Lsm1-7 complex","volume":"26","author":"Lobel","year":"2020","journal-title":"RNA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"iyac105","DOI":"10.1093\/genetics\/iyac105","article-title":"A distinct P-body-like granule is induced in response to the disruption of microtubule integrity in Saccharomyces cerevisiae","volume":"222","author":"Hurst","year":"2022","journal-title":"Genetics"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"9314","DOI":"10.1093\/nar\/gkad584","article-title":"mRNA decapping activators Pat1 and Dhh1 regulate transcript abundance and translation to tune cellular responses to nutrient availability","volume":"51","author":"Vijjamarri","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/yea.2968","article-title":"Subcellular localization and interaction network of the mRNA decay activator Pat1 upon UV stress","volume":"30","author":"Davin","year":"2013","journal-title":"Yeast"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.celrep.2017.06.091","article-title":"Dual RNA Processing Roles of Pat1b via Cytoplasmic Lsm1-7 and Nuclear Lsm2-8 Complexes","volume":"20","author":"Vindry","year":"2017","journal-title":"Cell Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e1557","DOI":"10.1002\/wrna.1557","article-title":"Pat1 RNA-binding proteins: Multitasking shuttling proteins","volume":"10","author":"Vindry","year":"2019","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6105","DOI":"10.1242\/jcs.113043","article-title":"The conserved P body component HPat\/Pat1 negatively regulates synaptic terminal growth at the larval Drosophila neuromuscular junction","volume":"125","author":"Pradhan","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.yexcr.2015.02.022","article-title":"PRMT1-mediated arginine methylation controls ATXN2L localization","volume":"334","author":"Kaehler","year":"2015","journal-title":"Exp. Cell Res."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Key, J., Almaguer-Mederos, L.E., Kandi, A.R., Sen, N.E., Gispert, S., Kopf, G., Meierhofer, D., and Auburger, G. (2025). ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation. Neurobiol. Dis., 209.","DOI":"10.1016\/j.nbd.2025.106903"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Key, J., Harter, P.N., Sen, N.E., Gradhand, E., Auburger, G., and Gispert, S. (2020). Mid-Gestation lethality of Atxn2l-Ablated Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145124"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"52","DOI":"10.2144\/00291bm09","article-title":"Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT)","volume":"29","author":"Truett","year":"2000","journal-title":"Biotechniques"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1002\/pmic.200401303","article-title":"PRIDE: The proteomics identifications database","volume":"5","author":"Martens","year":"2005","journal-title":"Proteomics"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.bbagrm.2018.01.019","article-title":"Beyond regulation of pol III: Role of MAF1 in growth, metabolism, aging and cancer","volume":"1861","author":"Zhang","year":"2018","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.devcel.2013.06.016","article-title":"REEP3\/4 ensure endoplasmic reticulum clearance from metaphase chromatin and proper nuclear envelope architecture","volume":"26","author":"Schlaitz","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.devcel.2013.07.018","article-title":"PREEParing for mitosis","volume":"26","author":"Burke","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/emboj\/20.1.187","article-title":"Sm protein-Sm site RNA interactions within the inner ring of the spliceosomal snRNP core structure","volume":"20","author":"Urlaub","year":"2001","journal-title":"EMBO J."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Decker, C.J., and Parker, R. (2012). P-bodies and stress granules: Possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a012286"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Irimia, M., Rukov, J.L., Penny, D., and Roy, S.W. (2007). Functional and evolutionary analysis of alternatively spliced genes is consistent with an early eukaryotic origin of alternative splicing. BMC Evol. Biol., 7.","DOI":"10.1186\/1471-2148-7-188"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1039\/c5mt00075k","article-title":"Selenium, selenoproteins and neurodegenerative diseases","volume":"7","author":"Cardoso","year":"2015","journal-title":"Metallomics"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"108043","DOI":"10.1016\/j.cclet.2022.108043","article-title":"Selenium and human nervous system","volume":"34","author":"Ding","year":"2023","journal-title":"Chin. Chem. Lett."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1006\/dbio.2002.0597","article-title":"Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: A tool for temporally regulated gene activation\/inactivation in the mouse","volume":"244","author":"Hayashi","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/gene.20011","article-title":"Spontaneous ectopic recombination in cell-type-specific Cre mice removes loxP-flanked marker cassettes in vivo","volume":"38","author":"Eckardt","year":"2004","journal-title":"Genesis"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Chakravarthy, S., Keck, T., Roelandse, M., Hartman, R., Jeromin, A., Perry, S., Hofer, S.B., Mrsic-Flogel, T., and Levelt, C.N. (2008). Cre-dependent expression of multiple transgenes in isolated neurons of the adult forebrain. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003059"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.stemcr.2018.08.004","article-title":"Analysis of Runx1 Using Induced Gene Ablation Reveals Its Essential Role in Pre-liver HSC Development and Limitations of an In Vivo Approach","volume":"11","author":"Senserrich","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.neuron.2008.03.001","article-title":"Behavioral phenotyping strategies for mutant mice","volume":"57","author":"Crawley","year":"2008","journal-title":"Neuron"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41467-021-27571-3","article-title":"Neuronal Yin Yang1 in the prefrontal cortex regulates transcriptional and behavioral responses to chronic stress in mice","volume":"13","author":"Kwon","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"RP87414","DOI":"10.7554\/eLife.87414.3","article-title":"Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function","volume":"12","author":"Mastwal","year":"2023","journal-title":"Elife"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.3390\/biom5031441","article-title":"Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins","volume":"5","author":"Bish","year":"2015","journal-title":"Biomolecules"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4459","DOI":"10.1016\/j.celrep.2020.02.076","article-title":"FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism","volume":"30","author":"Shah","year":"2020","journal-title":"Cell Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41586-022-04436-3","article-title":"TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A","volume":"603","author":"Brown","year":"2022","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e14316","DOI":"10.1111\/acel.14316","article-title":"Cooperative nuclear action of RNA-binding proteins PSF and G3BP2 to sustain neuronal cell viability is decreased in aging and dementia","volume":"23","author":"Takayama","year":"2024","journal-title":"Aging Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/dvg.20256","article-title":"Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice","volume":"44","author":"Goebbels","year":"2006","journal-title":"Genesis"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/cr.2017.55","article-title":"5-methylcytosine promotes mRNA export\u2014NSUN2 as the methyltransferase and ALYREF as an m(5)C reader","volume":"27","author":"Yang","year":"2017","journal-title":"Cell Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/s41556-019-0361-y","article-title":"5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs","volume":"21","author":"Chen","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"8189","DOI":"10.1073\/pnas.88.18.8189","article-title":"Primary structure of a human arginine-rich nuclear protein that colocalizes with spliceosome components","volume":"88","author":"Chaudhary","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1111\/j.1742-4658.2011.08274.x","article-title":"Shuttling SR proteins: More than splicing factors","volume":"278","author":"Twyffels","year":"2011","journal-title":"FEBS J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"5400","DOI":"10.1128\/MCB.16.10.5400","article-title":"Functional properties of p54, a novel SR protein active in constitutive and alternative splicing","volume":"16","author":"Zhang","year":"1996","journal-title":"Mol. Cell Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"5425","DOI":"10.1128\/MCB.18.9.5425","article-title":"A role for SRp54 during intron bridging of small introns with pyrimidine tracts upstream of the branch point","volume":"18","author":"Kennedy","year":"1998","journal-title":"Mol. Cell Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.tig.2020.10.008","article-title":"Anything but Ordinary\u2014Emerging Splicing Mechanisms in Eukaryotic Gene Regulation","volume":"37","author":"Gehring","year":"2021","journal-title":"Trends Genet."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/19\/1532\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T14:21:08Z","timestamp":1759242068000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/19\/1532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":114,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["cells14191532"],"URL":"https:\/\/doi.org\/10.3390\/cells14191532","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,9,30]]}}}