{"doi":"10.14336/ad.2025.1220","title":"Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases","abstract":"Phosphorylated ubiquitin (pS65-Ub) is generated by the kinase-ligase pair PINK1-Parkin to selectively label damaged mitochondria for degradation via the autophagy-lysosome system (mitophagy). Consistent with increasing mitochondrial and lysosomal dysfunctions, pS65-Ub accumulates with aging in human autopsy brain and in mice. pS65-Ub levels are strongly and independently elevated in brains from subjects with Alzheimer's or Parkinson's disease compared to age-matched, neurologically normal controls. Furthermore, pS65-Ub levels have been used to identify disease risk and potential resilience factors in cells and in human brain. However, it remains unknown whether pS65-Ub measured in biofluids may also be suitable as a clinical biomarker. Here, we used a validated sandwich ELISA based on the Mesoscale discovery platform to assess pS65-Ub levels in over 1500 plasma samples from different cohorts across a spectrum of mild cognitive impairment, Alzheimer's disease, or Parkinson's disease. We further analyzed almost 150 CSF samples from two independent case-control series with Parkinson's disease to determine whether pS65-Ub levels are associated with disease status and other clinical parameters. While pS65-Ub levels are significantly changed with disease compared to controls in certain samples, current measurements in plasma are not sufficiently discriminatory to serve as a robust diagnostic marker. However, in CSF, pS65-Ub levels were decreased in patients with Parkinson's disease compared to controls, and there was better discrimination between these groups. Our data indicate that pS65-Ub shows promise as a biomarker in CSF but will require further replication in larger cohorts and possibly in combination with additional other measures.","journal":"Aging and Disease","year":2025,"id":549505,"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":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":314467,"name":"Jens O. Watzlawik","orcid":"0000-0003-0610-0267","position":1,"is_corresponding":false},{"id":54748,"name":"Michael G. Heckman","orcid":"0000-0003-3770-9331","position":2,"is_corresponding":false},{"id":1443713,"name":"Sophia G. Blumenfeld","orcid":"0009-0009-3783-343X","position":3,"is_corresponding":false},{"id":299643,"name":"Michael J. Rigby","orcid":"0000-0001-8809-2648","position":4,"is_corresponding":false},{"id":1444236,"name":"Mohammed Kehili","orcid":null,"position":5,"is_corresponding":false},{"id":17495,"name":"Katja Lohmann","orcid":"0000-0002-5121-1460","position":6,"is_corresponding":false},{"id":17492,"name":"Christine Klein","orcid":"0000-0003-2102-3431","position":7,"is_corresponding":false},{"id":299707,"name":"Derek P. Narendra","orcid":"0000-0002-8696-9108","position":8,"is_corresponding":false},{"id":271547,"name":"Clemens R. Scherzer","orcid":"0000-0002-0567-9193","position":9,"is_corresponding":false},{"id":776,"name":"Nilüfer Ertekin‐Taner","orcid":"0000-0003-4436-8889","position":10,"is_corresponding":false},{"id":1228752,"name":"Neill R Graff-Radford","orcid":null,"position":11,"is_corresponding":false},{"id":17548,"name":"Zbigniew K. Wszołek","orcid":"0000-0001-5487-1053","position":12,"is_corresponding":false},{"id":17435,"name":"Owen A. Ross","orcid":"0000-0003-4813-756X","position":13,"is_corresponding":false},{"id":314474,"name":"Wolfdieter Springer","orcid":"0000-0002-1178-3149","position":14,"is_corresponding":false},{"id":314473,"name":"Fabienne C. Fiesel","orcid":"0000-0002-1919-9676","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:54:07.823422Z","pmid":"41400571","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":[]}