{"doi":"10.1124/molpharm.121.000301","title":"Therapeutic Neuroprotection by an Engineered Neurotrophin that Selectively Activates Tropomyosin Receptor Kinase (Trk) Family Neurotrophin Receptors but Not the p75 Neurotrophin Receptor","abstract":null,"journal":"Molecular Pharmacology","year":2021,"id":591510,"datarank":0.39828923397144667,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.06870554737101368,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.06870554737101368,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":5,"citers_with_citation_signal":4,"citers_with_endowment":4,"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":1513408,"name":"Alba Galan","orcid":null,"position":1,"is_corresponding":false},{"id":1513409,"name":"Sairey Siegel","orcid":null,"position":2,"is_corresponding":false},{"id":1513410,"name":"Stephanie Szobota","orcid":null,"position":3,"is_corresponding":false},{"id":1513411,"name":"Marinko V. Sarunic","orcid":null,"position":4,"is_corresponding":false},{"id":1513412,"name":"Alan C. Foster","orcid":null,"position":5,"is_corresponding":false},{"id":1513413,"name":"H. Uri Saragovi","orcid":null,"position":6,"is_corresponding":false},{"id":1513407,"name":"Fouad Brahimi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Therapeutic Neuroprotection by an Engineered Neurotrophin that Selectively Activates Tropomyosin Receptor Kinase (Trk) Family Neurotrophin Receptors but Not the p75 Neurotrophin Receptor","abstract":"The neurotrophin growth factors bind and activate two types of cell surface receptors: the tropomyosin receptor kinase (Trk) family and p75. TrkA, TrkB, and TrkC are bound preferentially by nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 (NT3), respectively, to activate neuroprotective signals. The p75 receptors are activated by all neurotrophins, and paradoxically in neurodegenerative disease p75 is upregulated and mediates neurotoxic signals. To test neuroprotection strategies, we engineered NT3 to broadly activate Trk receptors (mutant D) or to reduce p75 binding (mutant RK). We also combined these features in a molecule that activates TrkA, TrkB, and TrkC but has reduced p75 binding (mutant DRK). In neurodegenerative disease mouse models in vivo, the DRK protein is a superior therapeutic agent compared with mutant D, mutant RK, and wild-type neurotrophins and protects a broader range of stressed neurons. This work rationalizes a therapeutic strategy based on the biology of each type of receptor, avoiding activation of p75 toxicity while broadly activating neuroprotection in stressed neuronal populations expressing different Trk receptors. SIGNIFICANCE STATEMENT: The neurotrophins nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 each can activate a tropomyosin receptor kinase (Trk) A, TrkB, or TrkC receptor, respectively, and all can activate a p75 receptor. Trks and p75 mediate opposite signals. We report the engineering of a protein that activates all Trks, combined with low p75 binding, as an effective therapeutic agent in vivo.","is_dataset_classified":null,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34470776","pmcid":null,"openalex_id":"https://openalex.org/W3197181042","authors":[],"funders":[{"funder_name":"CIHR","grant_id":"","title":null},{"funder_name":"CIHR","grant_id":"","title":null}],"total_grants":2,"fwci":0.4796,"citation_percentile":0.54178941,"influential_citations":0,"citation_trend":[{"year":2022,"count":2},{"year":2023,"count":1},{"year":2024,"count":2},{"year":2025,"count":2}],"oa_status":"bronze","license":"https://www.elsevier.com/legal/tdmrep-license","oa_locations":[{"url":"https://molpharm.aspetjournals.org/content/molpharm/100/5/491.full.pdf","host_type":"journal"},{"url":"https://molpharm.aspetjournals.org/content/molpharm/100/5/491.full.pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0026895X24011751?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0026895X24011751?httpAccept=text/plain","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1124/molpharm.121.000301","host_type":"publisher"},{"url":"https://doi.org/10.1124/molpharm.121.000301","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34470776","host_type":"repository"}],"fields_of_study":["Nerve injury and regeneration","RNA Interference and Gene Delivery","Signaling Pathways in Disease","Animals","Axotomy","Diabetic Neuropathies","Dose-Response Relationship, Drug","HEK293 Cells","Humans","Male","Mice","Mice, Inbred C57BL","NIH 3T3 Cells","Nerve Growth Factors","Nerve Tissue Proteins","Neuroprotection","Optic Nerve","Protein Engineering","Receptor, trkA","Receptors, Growth Factor"],"mesh_terms":["Neuroprotection","Animals","Diabetic Neuropathies","Dose-Response Relationship, Drug","Humans","Male","Mice, Inbred C57BL","Nerve Growth Factors","Nerve Tissue Proteins","Optic Nerve","Protein Engineering","Receptors, Growth Factor","Axotomy","Receptor, trkA","NIH 3T3 Cells","Mice","HEK293 Cells"],"keywords":["Trk receptor","Tropomyosin receptor kinase A","Neurotrophin","Low-affinity nerve growth factor receptor","Tropomyosin receptor kinase C","Tropomyosin receptor kinase B","Neuroprotection","Biology","Nerve growth factor","Cell biology","Receptor","Neurotrophic factors","Neuroscience","Growth factor","Biochemistry","Platelet-derived growth factor receptor"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Gender equality"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-25T17:08:31.050050Z","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":[]}