title: Systems-based analyses of brain regions functionally impacted in Parkinson's disease reveals underlying causal mechanisms.
abstract: Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum, and cortex are functionally connected with increasing degrees of alpha-synuclein pathology in Parkinson's disease. We undertook functional and causal pathway analysis of gene expression and proteomic alterations in these three regions, and the data revealed pathways that correlated with disease progression. In addition, microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release, and these and other changes were reflected across all brain regions. Importantly, subsets of these changes were replicated in Parkinson's disease blood; suggesting peripheral tissue may provide important avenues for understanding and measuring disease status and progression. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changes that accompany functional loss and alpha-synuclein pathology in Parkinson's disease, and may be instrumental to understand, diagnose and follow Parkinson's disease progression.
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Brigit E
authors.initials: BE
authors.lastname: Riley
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Shyra J
authors.initials: SJ
authors.lastname: Gardai
authors.affiliation: Thomson Reuters, Carlsbad, California, United States of America.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Emig-Agius
authors.affiliation: Thomson Reuters, Carlsbad, California, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Bessarabova
authors.affiliation: Thomson Reuters, Carlsbad, California, United States of America.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Ivliev
authors.forename: Birgitt
authors.initials: B
authors.lastname: Schüle
authors.affiliation: The Parkinson's Institute, Sunnyvale, California, United States of America.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schüle
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Wallace
authors.affiliation: Neuroscience Research Australia and the University of New South Wales, Sydney, N.S.W., Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: The Parkinson's Institute, Sunnyvale, California, United States of America.
authors.forename: J William
authors.initials: JW
authors.lastname: Langston
authors.affiliation: Thomson Reuters, Carlsbad, California, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Braxton
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Ted
authors.initials: T
authors.lastname: Yednock
authors.affiliation: SRI International, Menlo Park, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Shaler
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Johnston
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D046228:Microarray Analysis; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; D051844:alpha-Synuclein