Proteomics as a Tool for Biomarker and Drug Target Discovery: Improving the Diagnosis and Treatment of Neurodegenerative Diseases

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About this Research Topic

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Background

As the number of people surviving beyond their 80s is growing dramatically, the number of people affected by age-related neurodegenerative diseases is expected to almost double over the next 20 years. Therefore, neurodegenerative diseases represent one of the major health challenges facing modern society with clear implications to associated healthcare costs. The lack of drugs that slow down or stop disease progression and the lack of specific, early prognostic biomarkers that that inform on disease evolution and detect at-risk individuals at the pre-symptomatic stage, when a drug would most likely be effective are two major obstacles in the diagnosis and treatment of neurodegenerative disease. To tackle these issues, improved understanding of the early pathogenic mechanisms that lead to neurodegenerative diseases is urgently needed. Over the last decade, technological advances have led to a gradual adoption by clinical researchers of proteomic strategies to identify proteoforms that are involved in early disease pathways, as potential drug targets and/or surrogate markers of disease pathogenesis and severity. Top-down proteomic approaches can yield highly biologically relevant results, as most proteins are present in different isoforms and subjected to numerous processing and post-translational modifications. Therefore, measuring the intact mass of proteins (Intact protein profiling) by mass spectrometry (MS) can inform on the direct presence and relative amount of the different proteoforms. The multiplexed quantification of selected proteins (PRM/SRM) and post-translational modification profiling provide clear advantages over traditional immuno-based assays, by increasing throughput and selectivity of specific disease-relevant proteoforms. Studies of protein dynamics, using techniques such as SILK can also be very informative. Recent advances in laser-microdissection, MS imaging and protein retrieval from paraffin-embedded tissue allow direct access to the affected tissue at autopsy, thereby opening the door to direct analysis of protein changes in brain tissue taken from areas that are most vulnerable to neurodegeneration by MS analysis (e.g., SWATH/DIA, shotgun). Patient-derived cerebrospinal fluid is an attractive alternative due to its direct access to the brain interstitial fluid, while blood and saliva may be more practical alternatives due to their less-invasive extraction procedure. Finally, induced pluripotent stem cell-derived neurons from affected patients represent an excellent source for studying mechanistic changes at the proteomic level (e.g., iTRAQ/TMT).

In this Research Topic, we welcome original contributions and review articles related to all studies that employ a proteomics strategy to address the critical need for diagnostic biomarkers and new drug targets for neurodegenerative diseases. We welcome both non-targeted and targeted proteomics studies with technology including but not limited to MS imaging, iTRAQ, SWATH, PRM, SRM. SILK or in silico network-based mapping with an emphasis on the use of patient-derived tissue or biofluids. We believe that this series of publications will stimulate conversation and advance research toward the potential prevention of these devastating diseases, by improving diagnosis, clinical trial design and drug target identification.

Keywords: Proteomics, biomarkers, neurodegeneration, diagnosis

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