Work

Discovery of Biomarkers for Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration From Human Cerebrospinal Fluid Using Mass Spectrometry-Based Proteomics

Year: 2021

Type: preprint

Abstract: BackgroundAmyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are progressive neurodegenerative diseases that share clinical and neuropathologic features. Critical to the mission of developing effective therapies for ALS and FTLD is the discovery of biomarkers that can illuminate shared mechanisms of neurodegeneration, which can then be evaluated for diagnostic, prognostic or pharmacodynamic value across the disease spectrums. MethodsHere, we merged unbiased discovery-based approaches and targeted quantitative comparative analyses between ALS and FTLD cerebrospinal fluid (CSF) to identify proteins that are altered in ALS and FTLD. ResultsDiscovery mass spectrometry (MS)-based proteomic approaches combined with tandem mass tags (TMT) quantification methods from 40 CSF samples comprising 20 patients with ALS and 20 healthy control (HC) individuals identified 19 differentially expressed candidate biomarker proteins after CSF fractionation. Notably, these candidate biomarkers included novel and previously identified proteins, thus validating our approach. Candidate biomarkers were subsequently examined using parallel reaction monitoring (PRM) MS methods on 80 unfractionated CSF samples comprising 30 patients with ALS, 19 patients with FTLD, and 31 HC individuals. Two candidate biomarkers (CNTNAP2 and CLSTN1) were downregulated in both ALS and FTLD compared to healthy controls, and 11 further candidate proteins were significantly downregulated in FTLD compared to HC. ConclusionsTaken together, this study identifies multiple novel proteins that are altered in ALS and FTLD, which provides the foundation for their evaluation and development as biomarkers for these diseases.

Source: Research Square

DOI: 10.21203/rs.3.rs-148356/v1

Authors: Sungtaek Oh, Yura Jang, Lawren VandeVrede, Adam L Boxer, Shanthini Sockanathan, Chan-Hyun Na

Institutions: Johns Hopkins University, University of California, San Francisco, UCSF Edward and Pearl Fein Memory and Aging Center

Language: English

Topic: Amyotrophic Lateral Sclerosis Research

Subfield: Clinical Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, University of California, San Francisco, National Institute on Aging, National Institute of Neurological Disorders and Stroke