Proteomic Profiling of Cranial (Superior) Cervical Ganglia Reveals Beta-Amyloid and Ubiquitin Proteasome System Perturbations in an Equine Multiple System Neuropathy.
Abstract: Equine grass sickness (EGS) is an acute, predominantly fatal, multiple system neuropathy of grazing horses with reported incidence rates of ∼2%. An apparently identical disease occurs in multiple species, including but not limited to cats, dogs, and rabbits. Although the precise etiology remains unclear, ultrastructural findings have suggested that the primary lesion lies in the glycoprotein biosynthetic pathway of specific neuronal populations. The goal of this study was therefore to identify the molecular processes underpinning neurodegeneration in EGS. Here, we use a bottom-up approach beginning with the application of modern proteomic tools to the analysis of cranial (superior) cervical ganglion (CCG, a consistently affected tissue) from EGS-affected patients and appropriate control cases postmortem. In what appears to be the proteomic application of modern proteomic tools to equine neuronal tissues and/or to an inherent neurodegenerative disease of large animals (not a model of human disease), we identified 2,311 proteins in CCG extracts, with 320 proteins increased and 186 decreased by greater than 20% relative to controls. Further examination of selected proteomic candidates by quantitative fluorescent Western blotting (QFWB) and subcellular expression profiling by immunohistochemistry highlighted a previously unreported dysregulation in proteins commonly associated with protein misfolding/aggregation responses seen in a myriad of human neurodegenerative conditions, including but not limited to amyloid precursor protein (APP), microtubule associated protein (Tau), and multiple components of the ubiquitin proteasome system (UPS). Differentially expressed proteins eligible for in silico pathway analysis clustered predominantly into the following biofunctions: (1) diseases and disorders, including; neurological disease and skeletal and muscular disorders and (2) molecular and cellular functions, including cellular assembly and organization, cell-to-cell signaling and interaction (including epinephrine, dopamine, and adrenergic signaling and receptor function), and small molecule biochemistry. Interestingly, while the biofunctions identified in this study may represent pathways underpinning EGS-induced neurodegeneration, this is also the first demonstration of potential molecular conservation (including previously unreported dysregulation of the UPS and APP) spanning the degenerative cascades from an apparently unrelated condition of large animals, to small animal models with altered neuronal vulnerability, and human neurological conditions. Importantly, this study highlights the feasibility and benefits of applying modern proteomic techniques to veterinary investigations of neurodegenerative processes in diseases of large animals.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication Date: 2015-09-13 PubMed ID: 26364976PubMed Central: PMC4638047DOI: 10.1074/mcp.M115.054635Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research uncovers the primary molecular processes that lead to neuronal degeneration in Equine grass sickness (EGS), a deadly neurological disease that affects grazing horses and similar species. The study discovered dysregulated proteins related to protein misfolding/aggregation conditions, often seen in human neurodegenerative diseases.
Study Objective and Methodology
- The study aimed to determine the molecular actions that trigger neurodegeneration in Equine grass sickness (EGS), an acute, fatal neurological disease that affects 2% of grazing horses and other species such as cats, dogs, and rabbits.
- The researchers used modern proteomic tools to analyze the cranial cervical ganglion (CCG), a tissue commonly affected by EGS, in both EGS-afflicted and control cases.
Key Findings
- From 2,311 proteins found in the CCG extracts, 320 showed a 20% increase and 186 exhibited a more than 20% decrease relative to control cases.
- A previously unknown dysregulation was discovered in proteins typically associated with protein misfolding and aggregation responses, commonly seen in various human neurodegenerative conditions. This involves amyloid precursor protein (APP), microtubule-associated protein (Tau), and multiple components of the ubiquitin proteasome system (UPS).
- Proteins with differential expressions pertinent to in silico pathway analysis primarily clustered into biofunctions such as neurological diseases, skeletal and muscular disorders, cellular assembly and organization, cell-to-cell signaling and interaction (considering molecules like epinephrine and dopamine, and adrenergic signaling and receptor function), and small molecule biochemistry.
Significance and Implications
- The study might represent the molecular pathways that cause EGS-induced neurodegeneration but also suggests molecular conservation—including the previously undetected dysregulation of UPS and APP—across a variety of conditions from large animals to small animal models with altered neuronal vulnerability, to human neurological conditions.
- Crucially, the research underscores the viability and advantages of applying modern proteomic techniques to veterinary inquiries into neurodegenerative processes in diseases affecting large animals.
Cite This Article
APA
McGorum BC, Pirie RS, Eaton SL, Keen JA, Cumyn EM, Arnott DM, Chen W, Lamont DJ, Graham LC, Llavero Hurtado M, Pemberton A, Wishart TM.
(2015).
Proteomic Profiling of Cranial (Superior) Cervical Ganglia Reveals Beta-Amyloid and Ubiquitin Proteasome System Perturbations in an Equine Multiple System Neuropathy.
Mol Cell Proteomics, 14(11), 3072-3086.
https://doi.org/10.1074/mcp.M115.054635 Publication
Researcher Affiliations
- From the Veterinary Clinical Sciences and bruce.mcgorum@ed.ac.uk T.M.Wishart@ed.ac.uk.
- From the Veterinary Clinical Sciences and.
- §Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK;
- From the Veterinary Clinical Sciences and.
- §Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK;
- §Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK;
- FingerPrints: Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK;
- FingerPrints: Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK;
- §Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK;
- §Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK;
- From the Veterinary Clinical Sciences and.
- §Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK; Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UK bruce.mcgorum@ed.ac.uk T.M.Wishart@ed.ac.uk.
MeSH Terms
- Amyloid beta-Protein Precursor / genetics
- Amyloid beta-Protein Precursor / metabolism
- Animals
- Female
- Ganglia, Sensory / chemistry
- Ganglia, Sensory / metabolism
- Ganglia, Sensory / pathology
- Gene Expression Profiling
- Gene Expression Regulation
- Gene Ontology
- Horse Diseases / diagnosis
- Horse Diseases / genetics
- Horse Diseases / metabolism
- Horse Diseases / pathology
- Horses
- Male
- Molecular Sequence Annotation
- Neurodegenerative Diseases / diagnosis
- Neurodegenerative Diseases / genetics
- Neurodegenerative Diseases / metabolism
- Neurodegenerative Diseases / pathology
- Proteasome Endopeptidase Complex / metabolism
- Proteomics
- Proteostasis Deficiencies / diagnosis
- Proteostasis Deficiencies / genetics
- Proteostasis Deficiencies / metabolism
- Proteostasis Deficiencies / pathology
- Ubiquitin / genetics
- Ubiquitin / metabolism
- tau Proteins / genetics
- tau Proteins / metabolism
Grant Funding
- 097945 / Wellcome Trust
- BBS/E/D/20251969 / Biotechnology and Biological Sciences Research Council
- MR/M010341/1 / Medical Research Council
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