Blood transcriptomics of drug-naïve sporadic Parkinson's disease patients.
BACKGROUND
Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder that is clinically defined in terms of motor symptoms. These are preceded by prodromal non-motor manifestations that prove the systemic nature of the disease. Identifying genes and pathways altered in living patients provide new information on the diagnosis and pathogenesis of sporadic PD.


METHODS
Changes in gene expression in the blood of 40 sporadic PD patients and 20 healthy controls ("Discovery set") were analyzed by taking advantage of the Affymetrix platform. Patients were at the onset of motor symptoms and before initiating any pharmacological treatment. Data analysis was performed by applying Ranking-Principal Component Analysis, PUMA and Significance Analysis of Microarrays. Functional annotations were assigned using GO, DAVID, GSEA to unveil significant enriched biological processes in the differentially expressed genes. The expressions of selected genes were validated using RT-qPCR and samples from an independent cohort of 12 patients and controls ("Validation set").


RESULTS
Gene expression profiling of blood samples discriminates PD patients from healthy controls and identifies differentially expressed genes in blood. The majority of these are also present in dopaminergic neurons of the Substantia Nigra, the key site of neurodegeneration. Together with neuronal apoptosis, lymphocyte activation and mitochondrial dysfunction, already found in previous analysis of PD blood and post-mortem brains, we unveiled transcriptome changes enriched in biological terms related to epigenetic modifications including chromatin remodeling and methylation. Candidate transcripts as CBX5, TCF3, MAN1C1 and DOCK10 were validated by RT-qPCR.


CONCLUSIONS
Our data support the use of blood transcriptomics to study neurodegenerative diseases. It identifies changes in crucial components of chromatin remodeling and methylation machineries as early events in sporadic PD suggesting epigenetics as target for therapeutic intervention.
Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. calliga@sissa.it.
Raffaella
R
Calligaris
Department of Medical Sciences, Neurology Unit, University of Trieste, Strada di Fiume 447, 34100, Trieste, Italy. m.banica@ymail.com.
Mihaela
M
Banica
Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. roncagli@sissa.it.|Present Address: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), CB10 1SD Hinxton, Cambridge, UK. roncagli@sissa.it.
Paola
P
Roncaglia
Department of Environmental and Life Sciences, University of Eastern Piedmont, Viale T. Michel 11, 15121, Alessandria, Italy. elisa.robotti@mfn.unipmn.it.
Elisa
E
Robotti
Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. sfinaurini@sissa.it.
Sara
S
Finaurini
Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. vlach@sissa.it.
Christina
C
Vlachouli
Department of Medical Sciences, Neurology Unit, University of Trieste, Strada di Fiume 447, 34100, Trieste, Italy. antonuttilucia@virgilio.it.
Lucia
L
Antonutti
Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, Naples, 80131, Italy. iorio@tigem.it.|Present Address: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), CB10 1SD Hinxton, Cambridge, UK. iorio@tigem.it.
Francesco
F
Iorio
Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, Naples, 80131, Italy. carissimo@tigem.it.
Annamaria
A
Carissimo
Department of Medical Sciences, Neurology Unit, University of Trieste, Strada di Fiume 447, 34100, Trieste, Italy. tatianacattaruzza@libero.it.
Tatiana
T
Cattaruzza
ITALTBS S.p.A., AREA Science Park, Padriciano, 99, 34149, Trieste, Italy. andrea.ceiner@eurotech.com.
Andrea
A
Ceiner
Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. lazarevic.dejan@hsr.it.|CBM Scrl - Consorzio per il Centro di Biomedicina Molecolare, Area Science Park, S.S.14, km 163.5, Basovizza, 34149, Trieste, Italy. lazarevic.dejan@hsr.it.
Dejan
D
Lazarevic
Department of Medical Sciences, Neurology Unit, University of Trieste, Strada di Fiume 447, 34100, Trieste, Italy. cucca.alberto@libero.it.
Alberto
A
Cucca
ITALTBS S.p.A., AREA Science Park, Padriciano, 99, 34149, Trieste, Italy. nicola.pangher@tbsgroup.com.
Nicola
N
Pangher
Department of Environmental and Life Sciences, University of Eastern Piedmont, Viale T. Michel 11, 15121, Alessandria, Italy. emilio.marengo@unipmn.it.
Emilio
E
Marengo
Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, Naples, 80131, Italy. dibernardo@tigem.it.|Department Computer Science & Systems, School of Engineering, University of Naples "Federico II", via Claudio 21, 80125, Naples, Italy. dibernardo@tigem.it.
Diego
D
di Bernardo
Department of Medical Sciences, Neurology Unit, University of Trieste, Strada di Fiume 447, 34100, Trieste, Italy. riccardo.pizzolato@gmail.com.
Gilberto
G
Pizzolato
Area of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136, Trieste, Italy. gustinci@sissa.it.
Stefano
S
Gustincich
D000368:Aged; D000090266:Chromobox Protein Homolog 5; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome / Q000235:genetics*