title: Quantitative Proteomic Analysis Reveals Similarities between Huntington's Disease (HD) and Huntington's Disease-Like 2 (HDL2) Human Brains.
abstract: The pathogenesis of HD and HDL2, similar progressive neurodegenerative disorders caused by expansion mutations, remains incompletely understood. No systematic quantitative proteomics studies, assessing global changes in HD or HDL2 human brain, were reported. To address this deficit, we used a stable isotope labeling-based approach to quantify the changes in protein abundances in the cortex of 12 HD and 12 control cases and, separately, of 6 HDL2 and 6 control cases. The quality of the tissues was assessed to minimize variability due to post mortem autolysis. We applied a robust median sweep algorithm to quantify protein abundance and performed statistical inference using moderated test statistics. 1211 proteins showed statistically significant fold changes between HD and control tissues; the differences in selected proteins were verified by Western blotting. Differentially abundant proteins were enriched in cellular pathways previously implicated in HD, including Rho-mediated, actin cytoskeleton and integrin signaling, mitochondrial dysfunction, endocytosis, axonal guidance, DNA/RNA processing, and protein transport. The abundance of 717 proteins significantly differed between control and HDL2 brain. Comparative analysis of the disease-associated changes in the HD and HDL2 proteomes revealed that similar pathways were altered, suggesting the commonality of pathogenesis between the two disorders.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , 600 North Wolfe Street, CMSC 8-121, Baltimore, Maryland 21287, United States.
authors.forename: Tamara
authors.initials: T
authors.lastname: Ratovitski
authors.affiliation: Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine , 733 North Broadway Street, Suite 371 BRB, Baltimore, Maryland 21205, United States.
authors.forename: Raghothama
authors.initials: R
authors.lastname: Chaerkady
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland 21205, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Kammers
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , 600 North Wolfe Street, CMSC 8-121, Baltimore, Maryland 21287, United States.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Stewart
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , 600 North Wolfe Street, CMSC 8-121, Baltimore, Maryland 21287, United States.
authors.forename: Anialak
authors.initials: A
authors.lastname: Zavala
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , 600 North Wolfe Street, CMSC 8-121, Baltimore, Maryland 21287, United States.
authors.forename: Dobrila D
authors.initials: DD
authors.lastname: Rudnicki
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , 600 North Wolfe Street, CMSC 8-121, Baltimore, Maryland 21287, United States.|Department of Neurology and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.affiliation: Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine , 733 North Broadway Street, Suite 371 BRB, Baltimore, Maryland 21205, United States.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cole
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine , 600 North Wolfe Street, CMSC 8-121, Baltimore, Maryland 21287, United States.|Department of Neurology and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.|Departments of Pharmacology and Neuroscience, Johns Hopkins University School of Medicine , Baltimore, Maryland 21287, United States.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
mesh_terms: D000465:Algorithms; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D002819:Chorea / Q000473:pathology*; D003072:Cognition Disorders / Q000473:pathology*; D003704:Dementia / Q000473:pathology*; D020271:Heredodegenerative Disorders, Nervous System / Q000473:pathology*; D006801:Humans; D006816:Huntington Disease / Q000473:pathology*; D007553:Isotope Labeling; D053858:Metabolic Networks and Pathways; D011506:Proteins / Q000032:analysis; D040901:Proteomics / Q000379:methods*
chemical_list: D011506:Proteins
keywords: Huntington’s disease; TMT; human brain; iTRAQ; neurodegenerative disorder; proteomics