Novel candidate blood-based transcriptional biomarkers of Machado-Joseph disease.
BACKGROUND
Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status.


METHODS
The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR).


RESULTS
Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls.


CONCLUSIONS
Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease. © 2015 International Parkinson and Movement Disorder Society.
Centre of Research in Natural Resources (CIRN), University of the Azores, Ponta Delgada, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
Mafalda
M
Raposo
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Conceição
C
Bettencourt
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Patrícia
P
Maciel
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA.
Fuying
F
Gao
Centre of Research in Natural Resources (CIRN), University of the Azores, Ponta Delgada, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
Amanda
A
Ramos
Centre of Research in Natural Resources (CIRN), University of the Azores, Ponta Delgada, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
Nadiya
N
Kazachkova
Department of Neurology, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal.
João
J
Vasconcelos
Department of Clinical Genetics, Hospital of D. Estefania, Lisbon, Portugal.
Teresa
T
Kay
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Ana João
AJ
Rodrigues
Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.|Hospital de Santo Espírito da Ilha Terceira, SEEBMO, Angra do Heroísmo, Portugal.
Bruno
B
Bettencourt
Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.|Hospital de Santo Espírito da Ilha Terceira, SEEBMO, Angra do Heroísmo, Portugal.
Jácome
J
Bruges-Armas
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA.
Daniel
D
Geschwind
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA.
Giovanni
G
Coppola
Centre of Research in Natural Resources (CIRN), University of the Azores, Ponta Delgada, Portugal.|Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
Manuela
M
Lima
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001394:Azores; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D017827:Machado-Joseph Disease / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D059467:Transcriptome / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D055815:Young Adult
D015415:Biomarkers
ataxin-3; gene expression; microarray; polyglutamine disease; spinocerebellar ataxia type 3