{"doi":"10.1101/2023.04.02.535298","title":"Bidirectional transcription at the <i>PPP2R2B</i> gene locus in spinocerebellar ataxia type 12","abstract":"Abstract OBJECTIVE Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by expansion of a CAG repeat in the PPP2R2B gene . Here we tested the hypothesis that the PPP2R2B antisense ( PPP2R2B-AS1 ) transcript containing a CUG repeat is expressed and contributes to SCA12 pathogenesis. METHODS Expression of PPP2R2B-AS1 transcript was detected in SCA12 human induced pluripotent stem cells (iPSCs), iPSC-derived NGN2 neurons, and SCA12 knock-in mouse brains using strand-specific RT-PCR (SS-RT-PCR). The tendency of expanded PPP2R2B-AS1 ( expPPP2R2B-AS1 ) RNA to form foci, a marker of toxic processes involving mutant RNAs, was examined in SCA12 cell models by fluorescence in situ hybridization. The toxic effect of expPPP2R2B-AS1 transcripts on SK-N-MC neuroblastoma cells was evaluated by caspase 3/7 activity. Western blot was used to examine the expression of repeat associated non-ATG-initiated (RAN) translation of expPPP2R2B-AS1 transcript in SK-N-MC cells. RESULTS The repeat region in PPP2R2B gene locus is bidirectionally transcribed in SCA12 iPSCs, iPSC-derived NGN2 neurons, and SCA12 mouse brains. Transfected expPPP2R2B-AS1 transcripts are toxic to SK-N-MC cells, and the toxicity may be mediated, at least in part, by the RNA secondary structure. The expPPP2R2B-AS1 transcripts form CUG RNA foci in SK-N-MC cells. expPPP2R2B-AS1 transcript is translated in the Alanine ORF via repeat-associated non-ATG (RAN) translation, which is diminished by single nucleotide interruptions within the CUG repeat, and MBNL1 overexpression. INTERPRETATION These findings suggest that PPP2R2B-AS1 contributes to SCA12 pathogenesis, and may therefore provide a novel therapeutic target for the disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":396134,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9653,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":574616,"name":"Hans B. Liu","orcid":"0000-0001-8911-5637","position":1,"is_corresponding":false},{"id":925205,"name":"Fatemeh Bakhsh","orcid":null,"position":2,"is_corresponding":false},{"id":636615,"name":"Bin Wu","orcid":"0000-0002-9442-3041","position":3,"is_corresponding":false},{"id":652078,"name":"Mingyao Ying","orcid":"0000-0002-6215-4959","position":4,"is_corresponding":false},{"id":681139,"name":"Russell L. Margolis","orcid":null,"position":5,"is_corresponding":false},{"id":751116,"name":"Pan P. Li","orcid":"0000-0001-6084-6348","position":6,"is_corresponding":false},{"id":1009965,"name":"Chengqian Zhou","orcid":"0000-0003-0431-275X","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:19:27.044553Z","pmid":"37066173","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}