{"doi":"10.1101/2025.07.09.663594","title":"Proteomic and\n                  <i>in silico</i>\n                  dissection of MetaAggregates in amyotrophic lateral sclerosis brains","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  RNA-binding proteins (RBPs), key translation regulators, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The pathological entities associated with ALS are known as “MetaAggregates”: heterogeneous coaggregates composed of amyloids, RBPs, and RNA G-quadruplexes (rG4s). In this study, to explore the molecular constituents of ALS-associated MetaAggregates, we developed a proteomic approach using a psoralen-conjugated RBP and crosslinked it with a biotinylated rG4 to enable the isolation of MetaAggregates from ALS brain extracts. Single-cell RNA-seq using\n                  <jats:italic>in vitro</jats:italic>\n                  ALS models identified ELAVL4 as a cytoplasmic RBP and revealed the enrichment of an IGFBP2-derived rG4 structure in ALS-specific neurons. Mass spectrometry and amyloidogenicity-based principal component analysis revealed 79 candidate proteins with roles in RNA processing, metabolism, trafficking, and stress responses. Docking simulations highlighted a subset of proteins with potential pro-aggregation characteristics, diverse cytosolic associations and functional links to RNA processing relevant to ALS. Through proteomic and\n                  <jats:italic>in silico</jats:italic>\n                  dissection of ALS-associated MetaAggregates, the findings of this study establish a conceptual framework for the exploration of unrecognized amyloidogenic drivers of neurodegeneration.\n                </jats:p>","journal":null,"year":null,"id":619815,"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":0,"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":1392804,"name":"Thi Hong Van Nguyen","orcid":"0000-0003-2133-9161","position":1,"is_corresponding":false},{"id":1136575,"name":"Nobuko Fujita","orcid":"0000-0002-4042-1403","position":2,"is_corresponding":false},{"id":1370857,"name":"Chioko Nagao","orcid":"0000-0002-7721-0642","position":3,"is_corresponding":false},{"id":1139959,"name":"Kenji Mizuguchi","orcid":"0000-0003-3021-7078","position":4,"is_corresponding":false},{"id":61826,"name":"Takumi Nishiuchi","orcid":"0000-0001-9429-5396","position":5,"is_corresponding":false},{"id":1599748,"name":"Yasuhiro Sakashita","orcid":null,"position":6,"is_corresponding":false},{"id":1599749,"name":"Moeko Noguchi-Shinohara","orcid":null,"position":7,"is_corresponding":false},{"id":392326,"name":"Kenjiro Ono","orcid":"0000-0001-8454-6155","position":8,"is_corresponding":false},{"id":1392803,"name":"Kazuma Murakami","orcid":"0000-0003-3152-1784","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Proteomic and\n                  <i>in silico</i>\n                  dissection of MetaAggregates in amyotrophic lateral sclerosis brains","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  RNA-binding proteins (RBPs), key translation regulators, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The pathological entities associated with ALS are known as “MetaAggregates”: heterogeneous coaggregates composed of amyloids, RBPs, and RNA G-quadruplexes (rG4s). In this study, to explore the molecular constituents of ALS-associated MetaAggregates, we developed a proteomic approach using a psoralen-conjugated RBP and crosslinked it with a biotinylated rG4 to enable the isolation of MetaAggregates from ALS brain extracts. Single-cell RNA-seq using\n                  <jats:italic>in vitro</jats:italic>\n                  ALS models identified ELAVL4 as a cytoplasmic RBP and revealed the enrichment of an IGFBP2-derived rG4 structure in ALS-specific neurons. Mass spectrometry and amyloidogenicity-based principal component analysis revealed 79 candidate proteins with roles in RNA processing, metabolism, trafficking, and stress responses. Docking simulations highlighted a subset of proteins with potential pro-aggregation characteristics, diverse cytosolic associations and functional links to RNA processing relevant to ALS. Through proteomic and\n                  <jats:italic>in silico</jats:italic>\n                  dissection of ALS-associated MetaAggregates, the findings of this study establish a conceptual framework for the exploration of unrecognized amyloidogenic drivers of neurodegeneration.\n                </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W4412355242","authors":[],"funders":[{"funder_name":"JSPS KAKENHI","grant_id":"23H03852 (KM)","title":null}],"total_grants":1,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/07/11/2025.07.09.663594.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/07/11/2025.07.09.663594.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2025.07.09.663594","host_type":"publisher"},{"url":"https://doi.org/10.1101/2025.07.09.663594","host_type":"repository"},{"url":"http://hdl.handle.net/2433/295734","host_type":"repository"}],"fields_of_study":["biodegradable polymer synthesis and properties"],"mesh_terms":[],"keywords":["Amyotrophic lateral sclerosis","In silico","Neuroscience","Dissection (medical)","Medicine","Computational biology","Physical medicine and rehabilitation","Biology","Anatomy","Pathology","Gene","Disease","Genetics"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T08:41:38.510723Z","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":[]}