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Title: C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease
Authors: Goodier, John L.
Soares, Alisha O.
Pereira, Gavin C.
DeVine, Lauren R.
Sanchez, Laura
Cole, Robert N.
García-Pérez, Jose Luis
metadata.dc.contributor.authoraffiliation: [Goodier,JL; Soares,AO; Pereira,GC] McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [DeVine,LR; Cole,RN] Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [Sanchez,L; García-Pérez,JL] GENYO. Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain. [García-Pérez,JL] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.
Keywords: Amyotrophic lateral sclerosis;Autophagy;Biomarker;Mass spectrometry;Proteasome;Stress granules;Ubiquitin;Esclerosis amiotrófica lateral;Autofagia;Biomarcadores;Espectrometría de masas;Complejo de la endopetidasa proteasomal;Ubiquitina;Proteína C9orf72
metadata.dc.subject.mesh: Medical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Spinal Cord Diseases::Amyotrophic Lateral Sclerosis
Medical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Autophagy
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Chemistry Techniques, Analytical::Mass Spectrometry
Medical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::Multienzyme Complexes::Proteasome Endopeptidase Complex
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Ubiquitins::Ubiquitin
Issue Date: 16-Jul-2020
Publisher: BioMed Central, Springer Nature
Citation: Goodier JL, Soares AO, Pereira GC, DeVine LR, Sanchez L, Cole RN, et al. C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease. Acta Neuropathol Commun. 2020 Jul 16;8(1):110
Abstract: A pathogenic GGGCCC hexanucleotide expansion in the first intron/promoter region of the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (ALS). The C9orf72 gene product forms a complex with SMCR8 (Smith-Magenis Syndrome Chromosome Region, Candidate 8) and WDR41 (WD Repeat domain 41) proteins. Recent studies have indicated roles for the complex in autophagy regulation, vesicle trafficking, and immune response in transgenic mice, however a direct connection with ALS etiology remains unclear. With the aim of increasing understanding of the multi-functional C9orf72-SMCR8-WDR41 complex, we determined by mass spectrometry analysis the proteins that directly associate with SMCR8. SMCR8 protein binds many components of the ubiquitin-proteasome system, and we demonstrate its poly-ubiquitination without obvious degradation. Evidence is also presented for localization of endogenous SMCR8 protein to cytoplasmic stress granules. However, in several cell lines we failed to reproduce previous observations that C9orf72 protein enters these granules. SMCR8 protein associates with many products of genes associated with various Mendelian neurological disorders in addition to ALS, implicating SMCR8-containing complexes in a range of neuropathologies. We reinforce previous observations that SMCR8 and C9orf72 protein levels are positively linked, and now show in vivo that SMCR8 protein levels are greatly reduced in brain tissues of C9orf72 gene expansion carrier individuals. While further study is required, these data suggest that SMCR8 protein level might prove a useful biomarker for the C9orf72 expansion in ALS.
metadata.dc.identifier.doi: 10.1186/s40478-020-00982-x
ISSN: 2051-5960 (Online)
Appears in Collections:01- Artículos - GENYO. Centro Pfizer-Andalucía de Genómica e Investigación Oncológica

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