{"doi":"10.3390/ijms22020901","title":"From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases","abstract":"<jats:p>A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin.</jats:p>","journal":"International Journal of Molecular Sciences","year":2021,"id":13767,"datarank":0.6707633172617373,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.26455578709640576,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.26455578709640576,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":12,"citers_with_citation_signal":10,"citers_with_endowment":10,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":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":111586,"name":"Ilia V. Baskakov","orcid":"0000-0003-2821-0942","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":2.70805020110221,"endowment":2.70805020110221,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"33477465","pmcid":"PMC7830165","openalex_id":"https://openalex.org/W3122747281","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"NS045585","title":null},{"funder_name":"National Institutes of Health","grant_id":"AI128925","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI128925","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS045585","title":null},{"funder_name":"National Institutes of Health","grant_id":"1R01AI128925-01A1","title":"Role of prion protein sialylation in prion diseases"},{"funder_name":"National Institutes of Health","grant_id":"5R01NS045585-07","title":"Self-Propagating Mechanism of Prion Diseases"}],"total_grants":6,"fwci":0.8141,"citation_percentile":0.70110385,"influential_citations":0,"citation_trend":[{"year":2022,"count":3},{"year":2023,"count":5},{"year":2024,"count":2},{"year":2025,"count":4}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/22/2/901/pdf?version=1610958147","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/22/2/901/pdf?version=1610958147","host_type":"GOLD"},{"url":"https://www.mdpi.com/1422-0067/22/2/901/pdf?version=1610958147","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/22/2/901/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms22020901","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/33477465","host_type":"repository"},{"url":"https://doaj.org/article/8edc31284f5a4822abd2e154606cec6d","host_type":"repository"},{"url":"https://dx.doi.org/10.3390/ijms22020901","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7830165","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC7830165","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC7830165?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.3390/ijms22020901","host_type":""}],"fields_of_study":["Prion Diseases and Protein Misfolding","Neurological diseases and metabolism","Alzheimer's disease research and treatments","Medicine","Biology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Humans","Neurodegenerative Diseases","Phenotype","Prion Proteins","Protein Conformation","Protein Processing, Post-Translational","Substrate Specificity","Synucleinopathies","Tauopathies","alpha-Synuclein","tau Proteins"],"mesh_terms":["Prion Proteins","Synucleinopathies","Humans","Phenotype","Protein Conformation","Protein Processing, Post-Translational","Substrate Specificity","tau Proteins","Neurodegenerative Diseases","Tauopathies","alpha-Synuclein"],"keywords":["Phenotype","Biology","Clinical phenotype","Disease","Genetics","Synucleinopathies","Computational biology","Gene isoform","Gene","Parkinson's disease","Alpha-synuclein","Medicine","Phosphorylation","Ubiquitination","Neurodegenerative diseases","Strains","Tau","α-synuclein","prion protein","Prion Disease","Parkinson’s Disease","Posttranslational Modifications","Alzheimer’s Diseases","N-linked Glycans","Protein Conformation","tau Proteins","Review","Prion Proteins","Substrate Specificity","Tauopathies","Humans","Protein Processing, Post-Translational"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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