title: Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease.
abstract: BACKGROUND
  Parkinson disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (SNCA) and other proteins in aggregates termed "Lewy Bodies" within neurons. PD has both genetic and environmental risk factors, and while processes leading to aberrant protein aggregation are unknown, past work points to abnormal levels of SNCA and other proteins. Although several genome-wide studies have been performed for PD, these have focused on DNA sequence variants by genome-wide association studies (GWAS) and on RNA levels (microarray transcriptomics), while genome-wide proteomics analysis has been lacking.
  
  
  METHODS
  This study employed two state-of-the-art technologies, three-stage Mass Spectrometry Tandem Mass Tag Proteomics (12 PD, 12 controls) and RNA-sequencing transcriptomics (29 PD, 44 controls), evaluated in the context of PD GWAS implicated loci and microarray transcriptomics (19 PD, 24 controls). The technologies applied for this study were performed in a set of overlapping prefrontal cortex (Brodmann area 9) samples obtained from PD patients and sex and age similar neurologically healthy controls.
  
  
  RESULTS
  After appropriate filters, proteomics robustly identified 3558 unique proteins, with 283 of these (7.9 %) significantly different between PD and controls (q-value < 0.05). RNA-sequencing identified 17,580 protein-coding genes, with 1095 of these (6.2 %) significantly different (FDR p-value < 0.05); only 166 of the FDR significant protein-coding genes (0.94 %) were present among the 3558 proteins characterized. Of these 166, eight genes (4.8 %) were significant in both studies, with the same direction of effect. Functional enrichment analysis of the proteomics results strongly supports mitochondrial-related pathways, while comparable analysis of the RNA-sequencing results implicates protein folding pathways and metallothioneins. Ten of the implicated genes or proteins co-localized to GWAS loci. Evidence implicating SNCA was stronger in proteomics than in RNA-sequencing analyses.
  
  
  CONCLUSIONS
  We report the largest analysis of proteomics in PD to date, and the first to combine this technology with RNA-sequencing to investigate GWAS implicated loci. Notably, differentially expressed protein-coding genes were more likely to not be characterized in the proteomics analysis, which lessens the ability to compare across platforms. Combining multiple genome-wide platforms offers novel insights into the pathological processes responsible for this disease by identifying pathways implicated across methodologies.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA. adumitri@bu.edu.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dumitriu
authors.affiliation: Proteostasis Therapeutics Inc., Cambridge, MA, 02139, USA. javadgolji@gmail.com.
authors.forename: Javad
authors.initials: J
authors.lastname: Golji
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA. labadorf@bu.edu.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Labadorf
authors.affiliation: Proteostasis Therapeutics Inc., Cambridge, MA, 02139, USA. gaobenbo@gmail.com.
authors.forename: Benbo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, 85351, USA. Thomas.Beach@bannerhealth.com.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA. rmyers@bu.edu.|Genome Science Institute, Boston University School of Medicine, Boston, MA, 02118, USA. rmyers@bu.edu.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.affiliation: Proteostasis Therapeutics Inc., Cambridge, MA, 02139, USA. Ken.Longo@proteostasis.com.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Longo
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA. jlatoure@bu.edu.
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Latourelle
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020869:Gene Expression Profiling / Q000379:methods*; D063990:Gene Ontology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D017510:Protein Folding; D040901:Proteomics / Q000379:methods*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D012333:RNA, Messenger