Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles.
The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention.
Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Niedersachsen, Germany.|Faculty of Medicine, University of Porto, Porto, Portugal.
Raquel
R
Pinho
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Leonor C
LC
Guedes
Department of Molecular Neuroscience, The Institute of Neurology, University College London, London, United Kingdom.
Lilach
L
Soreq
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Patrícia P
PP
Lobo
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Tiago
T
Mestre
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Miguel
M
Coelho
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Mário M
MM
Rosa
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Nilza
N
Gonçalves
Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Niedersachsen, Germany.
Pauline
P
Wales
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Tiago
T
Mendes
Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Niedersachsen, Germany.
Ellen
E
Gerhardt
Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Niedersachsen, Germany.
Christiane
C
Fahlbusch
Department Clinical Genetics, Erasmus MC, Rotterdam, South Holland, The Netherlands.
Vincenzo
V
Bonifati
Institute of Medical Genetics and Applied Genomics, Eberhard-Karls-University Tübingen, Tübingen, Baden-Württemberg, Germany.
Michael
M
Bonin
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Gabriel
G
Miltenberger-Miltényi
Department for Functional Genomics, Center for Translational and Clinical Research, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia.
Fran
F
Borovecki
The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.|Department of Biological Chemistry, The Life Sciences Institute, Jerusalem, Israel.
Hermona
H
Soreq
Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Joaquim J
JJ
Ferreira
Department of NeuroDegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Niedersachsen, Germany.|CEDOC, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
Tiago
T
F Outeiro
D002478:Cells, Cultured; D016000:Cluster Analysis; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010300:Parkinson Disease / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
C497604:SNCA protein, human; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2