{"doi":"10.1016/j.neuron.2023.02.033","title":"Neuronal identity defines α-synuclein and tau toxicity","abstract":"Pathogenic α-synuclein and tau are critical drivers of neurodegeneration, and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type-intrinsic property or a consequence of increased expression levels remains elusive. Here, we explore cell-type-specific α-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain-wide single-cell RNA sequencing of >200 live neuron types in fruit flies to determine which cellular environments react most to α-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of α-synuclein or tau expression levels. Comparing vulnerable with resilient neurons in Drosophila enabled us to predict numerous human neuron subtypes with increased intrinsic susceptibility to pathogenic α-synuclein or tau. By uncovering synapse- and Ca 2+ homeostasis-related genes as tau toxicity modifiers, our work paves the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.","journal":"Neuron","year":2023,"id":318981,"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":59,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9336,"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":1004455,"name":"Sabine Kuenen","orcid":"0000-0001-9135-5293","position":1,"is_corresponding":false},{"id":1004456,"name":"Nils Schoovaerts","orcid":"0000-0003-0990-6784","position":2,"is_corresponding":false},{"id":1004457,"name":"Natalie Kaempf","orcid":"0000-0002-5466-3972","position":3,"is_corresponding":false},{"id":1027604,"name":"Jeevanjot Singh","orcid":null,"position":4,"is_corresponding":false},{"id":302318,"name":"Jasper Janssens","orcid":"0000-0001-9264-0782","position":5,"is_corresponding":false},{"id":1004458,"name":"Jef Swerts","orcid":"0000-0002-3380-6030","position":6,"is_corresponding":false},{"id":1004459,"name":"Eliana Nachman","orcid":"0000-0002-2069-6469","position":7,"is_corresponding":false},{"id":806637,"name":"Carles Calatayud","orcid":"0000-0003-0032-4198","position":8,"is_corresponding":false},{"id":15495,"name":"Stein Aerts","orcid":"0000-0002-8006-0315","position":9,"is_corresponding":false},{"id":15482,"name":"Suresh Poovathingal","orcid":"0000-0002-3236-2255","position":10,"is_corresponding":false},{"id":806638,"name":"Patrik Verstreken","orcid":"0000-0002-5073-5393","position":11,"is_corresponding":false},{"id":1004454,"name":"Roman Praschberger","orcid":"0000-0001-7162-2403","position":0,"is_corresponding":true}],"reference_count":123,"raw_metadata":null,"created_at":"2026-07-19T01:07:06.454099Z","pmid":"36948206","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":[]}