Proteomic analysis of urinary extracellular vesicles reveal biomarkers for neurologic disease.
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2019-07
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BACKGROUND:Extracellular vesicles (EVs) harbor thousands of proteins that hold promise for biomarker development. Usually difficult to purify, EVs in urine are relatively easily obtained and have demonstrated efficacy for kidney disease prediction. Herein, we further characterize the proteome of urinary EVs to explore the potential for biomarkers unrelated to kidney dysfunction, focusing on Parkinson's disease (PD). METHODS:Using a quantitative mass spectrometry approach, we measured urinary EV proteins from a discovery cohort of 50 subjects. EVs in urine were classified into subgroups and EV proteins were ranked by abundance and variability over time. Enriched pathways and ontologies in stable EV proteins were identified and proteins that predict PD were further measured in a cohort of 108 subjects. FINDINGS:Hundreds of commonly expressed urinary EV proteins with stable expression over time were distinguished from proteins with high variability. Bioinformatic analyses reveal a striking enrichment of endolysosomal proteins linked to Parkinson's, Alzheimer's, and Huntington's disease. Tissue and biofluid enrichment analyses show broad representation of EVs from across the body without bias towards kidney or urine proteins. Among the proteins linked to neurological diseases, SNAP23 and calbindin were the most elevated in PD cases with 86% prediction success for disease diagnosis in the discovery cohort and 76% prediction success in the replication cohort. INTERPRETATION:Urinary EVs are an underutilized but highly accessible resource for biomarker discovery with particular promise for neurological diseases like PD.
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Wang, Shijie, Kyoko Kojima, James A Mobley and Andrew B West (2019). Proteomic analysis of urinary extracellular vesicles reveal biomarkers for neurologic disease. EBioMedicine, 45. pp. 351–361. 10.1016/j.ebiom.2019.06.021 Retrieved from https://hdl.handle.net/10161/19466.
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Andrew Bradley West
I am a tenured Professor with a primary appointment in Pharmacology and Cancer Biology, secondary appointments in Neurology and Neurobiology, and I serve as the director of the Duke Center for Neurodegeneration and Neurotherapeutics. Our main research efforts in the laboratory have focused on LRRK2 and alpha-synuclein in critical mechanisms and biomarkers in neurodegeneration and as possible therapeutic targets for disease modification strategies. I am a founding member of the NINDS Parkinson Disease Biomarker Program (PDBP) steering committee, a past member of the Executive Scientific Advisory Board at the Michael J. Fox Foundation (MJFF), current member of the NSD-B study section for the NINDS Office of Translational Research, and I am a board-reviewing editor for neurodegeneration research for eLife.
In training, i performed undergraduate research in the laboratory of Todd Golde focused on mechanisms of Ab toxicity, thesis work in the laboratories of John Hardy and Matthew Farrer (Mayo Clinic Parkinson’s Udall Center) focused on the genetics and genomics of parkin-linked PD, and post-doctoral work with Nigel Maidment (UCLA Udall Center) and Ted and Valina Dawson (Johns Hopkins Parkinson Udall Center) focused on LRRK2-linked Parkinson disease. I was previously an F31 and F32 individual NRSA recipient and was selected in the first wave of NIH’s K99 pipeline in 2006. Funding from both NINDS and MJFF has been continuous since the West laboratory opened in Birmingham in 2008 and continued with the move to Duke University in late 2018.
I have authored more than 100 publications characterizing biochemical mechanisms underlying neurodegeneration and neurodevelopmental disorders. The West laboratory serves as a hub for LRRK2 and a-synuclein research through freely sharing novel antibodies, recombinant proteins, DNA plasmids, viral constructs, animals, and protocols with dozens of laboratories and pharmaceutical
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