{"doi":"10.1101/2025.03.19.644182","title":"PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinson’s disease","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in\n                  <jats:italic>LRRK2</jats:italic>\n                  are linked to Parkinson’s disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of\n                  <jats:italic>Ppm1m</jats:italic>\n                  leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare\n                  <jats:italic>PPM1M</jats:italic>\n                  mutation in patients with Parkinson’s disease that is catalytically inactive when tested\n                  <jats:italic>in vitro</jats:italic>\n                  and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson’s disease.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Teaser</jats:title>\n                  <jats:p>Parkinson’s linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.</jats:p>\n                </jats:sec>","journal":null,"year":null,"id":610794,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"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":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1401802,"name":"Neringa Pratuseviciute","orcid":"0000-0002-1124-8699","position":1,"is_corresponding":false},{"id":1325522,"name":"Yu‐En Lin","orcid":"0000-0002-5848-5405","position":2,"is_corresponding":false},{"id":1063793,"name":"Ayan Adhikari","orcid":"0000-0002-8525-3263","position":3,"is_corresponding":false},{"id":1023941,"name":"Wondwossen M Yeshaw","orcid":"0000-0002-3134-3458","position":4,"is_corresponding":false},{"id":1401803,"name":"Chloe Flitton","orcid":"0009-0005-2778-8381","position":5,"is_corresponding":false},{"id":1401804,"name":"Pemba Sherpa","orcid":"0000-0002-4678-0001","position":6,"is_corresponding":false},{"id":635904,"name":"Francesca Tonelli","orcid":"0000-0002-4600-6630","position":7,"is_corresponding":false},{"id":252025,"name":"Irena Rektorová","orcid":"0000-0002-5455-4573","position":8,"is_corresponding":false},{"id":17422,"name":"Timothy Lynch","orcid":"0000-0002-2380-8737","position":9,"is_corresponding":false},{"id":314471,"name":"Joanna Siuda","orcid":"0000-0002-0340-660X","position":10,"is_corresponding":false},{"id":1570549,"name":"Monika Rudzińska-Bar","orcid":null,"position":11,"is_corresponding":false},{"id":733638,"name":"O. R. Pulyk","orcid":"0000-0002-8717-047X","position":12,"is_corresponding":false},{"id":406939,"name":"Peter Bauer","orcid":"0000-0001-9414-4555","position":13,"is_corresponding":false},{"id":325979,"name":"Christian Beetz","orcid":"0000-0001-7061-2895","position":14,"is_corresponding":false},{"id":54753,"name":"Dennis W. Dickson","orcid":"0000-0001-7189-7917","position":15,"is_corresponding":false},{"id":17435,"name":"Owen A. Ross","orcid":"0000-0003-4813-756X","position":16,"is_corresponding":false},{"id":17548,"name":"Zbigniew K. Wszołek","orcid":"0000-0001-5487-1053","position":17,"is_corresponding":false},{"id":17492,"name":"Christine Klein","orcid":"0000-0003-2102-3431","position":18,"is_corresponding":false},{"id":56224,"name":"Alexander Zimprich","orcid":"0000-0002-1668-5177","position":19,"is_corresponding":false},{"id":285688,"name":"Dario R. Alessi","orcid":"0000-0002-2140-9185","position":20,"is_corresponding":false},{"id":860476,"name":"Esther Sammler","orcid":"0000-0003-3218-7116","position":21,"is_corresponding":false},{"id":473584,"name":"Suzanne R. Pfeffer","orcid":"0000-0002-6462-984X","position":22,"is_corresponding":false},{"id":907286,"name":"Claire Y Chiang","orcid":"0000-0002-0999-9856","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinson’s disease","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in\n                  <jats:italic>LRRK2</jats:italic>\n                  are linked to Parkinson’s disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of\n                  <jats:italic>Ppm1m</jats:italic>\n                  leads to primary cilia loss in striatal cholinergic interneurons. We have also identified a rare\n                  <jats:italic>PPM1M</jats:italic>\n                  mutation in patients with Parkinson’s disease that is catalytically inactive when tested\n                  <jats:italic>in vitro</jats:italic>\n                  and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson’s disease.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>Teaser</jats:title>\n                  <jats:p>Parkinson’s linked Rab phosphorylation is reversed by PPM1M; the inactive D440N variant is implicated in rare patient cases.</jats:p>\n                </jats:sec>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40166354","pmcid":null,"openalex_id":"https://openalex.org/W4408707008","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2025,"count":2}],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/03/19/2025.03.19.644182.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/03/19/2025.03.19.644182.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2025.03.19.644182","host_type":"publisher"},{"url":"https://doi.org/10.1101/2025.03.19.644182","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40166354","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11957146","host_type":"repository"},{"url":"https://pub.dzne.de/record/280915","host_type":"repository"}],"fields_of_study":["Cellular transport and secretion","Microtubule and mitosis dynamics","Retinal Development and Disorders"],"mesh_terms":[],"keywords":["LRRK2","GTPase","Phosphatase","Rab","Knockout mouse","Cell biology","Phosphorylation","Kinase","Biology","Conditional gene knockout","Disease","Mutation","Phenotype","Cancer research","Receptor","Medicine","Genetics","Gene","Internal medicine"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-01T11:27:58.163407Z","pmid":null,"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":[]}