Agosti C.

Barlati S.

Borsani G.

Bozzato A.

Ferraboli S.

Marchina E.

Padovani A.

Rozzini L.

MARCHINA, Eleonora

FERRABOLI, Sergio

ROZZINI, Luca

BORSANI, Giuseppe

BARLATI, Sergio

PADOVANI, Alessandro

Archivio istituzionale della ricerca - Università di Brescia

Funding This study was supported by a Pfizer Neuroscience Research Grant.H05 GENE EXPRESSION PROFILE IN FIBROBLASTS OFHUNTINGTON’S DISEASE PATIENTS AND CONTROLSdoi:10.1136/jnnp.2010.222653.51E Marchina, 1A Bozzato, 1S Ferraboli, 2C Agosti, 2L Rozzini, 1G Borsani, 1S Barlati,2A Padovani. 1Biology and Genetics Unit, Department of Biomedical Sciences andBiotechnologies, University of Brescia, Brescia, Italy; 2Neurology Unit, Department ofMedical and Surgical Sciences, University of Brescia, Brescia, ItalyHuntington’s disease (HD), MIM 143100, is a dominantly inheritedprogressive neurodegenerative disorder characterised by motor,behavioural and cognitive dysfunction, caused by an expandedCAG repeat region in exon 1 of the HTT gene. This mutationresults in the presence of an abnormally long polyglutamine tractin the encoded protein, huntingtin. Research into this disorder hasconventionally focused on neurological symptoms and brainpathology, particularly neurodegeneration in the basal ganglia andcerebral cortex. Mutant huntingtin is, however, ubiquitouslyexpressed throughout the body. Contrary to earlier thinking, HD isalso associated with abnormalities in peripheral tissues. Due toobvious problems in obtaining brain tissue, these peripheral tissuescan be studied to elucidate pathogenetic mechanism (still not wellunderstood) of the disease as well as identifying disease biomarkers.Peripheral tissue dermal ﬁbroblasts, which have the same ecto-dermal origin as CNS cells, may represent an alternative source forbiological studies. Furthermore, contrary to peripheral blood cells,this cell type is not directly exposed to drugs. We performed geneexpression proﬁle analysis of human ﬁbroblasts obtained from HDpatients and healthy controls matched by age and sex. The studywas performed using the whole genome Affymetrix HG U133 plus2.0 arrays. Preliminary data obtained indicate that 451 genes areupregulated twofold or greater in patients compared with controlswhile 17 are downregulated. This study allowed us to evidence themodulation at the transcriptional level of a discrete number ofgenes relevant in biological processes which are altered in thediseasedprocesses such as transcription and its regulation, apop-tosis, regulation of actin cytoskeleton, inositol phosphate meta-bolism and vesicle mediated transport. We plan to extend this typeof analysis to a larger number of cases and controls and to conﬁrmthe differential expression of interesting genes both at the RNA andprotein levels. The data generated by this study could provide novelclues on the Huntington pathogenesis and lead to the identiﬁcationof a set of mRNAs that appear to be useful as biomarkers of thedisease.H06 CROSS SECTIONAL AND LONGITUDINAL 3T MAGNETICRESONANCE SPECTROSCOPY IN A TRACK-HD COHORTOF INDIVIDUALS WITH PREMANIFEST AND EARLYHUNTINGTON’S DISEASEdoi:10.1136/jnnp.2010.222653.61A Sturrock, 2C Laule, 1J Decolongon, 1R dar Santos, 1A J Coleman, 1S Creighton,3N Bechtel, 3R Reilmann, 1M R Hayden, 4S J Tabrizi, 2A L Mackay, 1B R Leavitt.1Department of Medical Genetics, University of British Columbia (UBC), Vancouver,British Columbia, Canada; 2UBC MRI Research Centre, University of British Columbia,Vancouver, British Columbia, Canada; 3Department of Neurology, University ofMu¨nster, Mu¨nster, Germany; 4UCL Institute of Neurology, University College London,London, UKBackground A potential biomarker role for magnetic resonancespectroscopy (MRS) in Huntington’s disease (HD) is unclear due toconﬂicting reports in the literature.Aim To investigate MRS as an HD biomarker through crosssectional and longitudinal examinations in a TRACK-HD studycohort.Methods Cross sectional MRS of the left putamen (at 3T ﬁeldstrength) was performed in the University of British ColumbiaTRACK-HD study cohort. 84 individuals (30 controls (C), 25 pre-HD (P), 29 early HD (E)) were scanned at baseline. 78 individuals(29 (C), 26 (P) and 23 (E)) underwent repeat MRS examination at1 year. Metabolites of interest were total N-acetyl aspartate(tNAA) and myo-inositol (MI); markers of neuronal health andgliosis.Results Baseline tNAA concentrations in early HD were lower thanin controls (mean (SD) 8.6 (0.7) mM (C) vs 7.3 (1.2) mM (E);p<0.001). MI was higher in early HD compared with controls (6.0(2.6) mM (E) vs 4.3 (1.4) mM (C); p<0.005). After 1 year, MIconcentrations remained 40% higher in early HD (6.0 (2.7) mM (E)vs 4.2 (1.1) mM (C); p<0.01). tNAA was still lower in early HD(p<0.001) but also in pre-HD (p<0.05) than controls (7.4 (0.9) mM(E) vs 8.2 (0.8) mM (P) vs 8.7 (0.6) mM (C)). Neither tNAA nor MIexhibited longitudinal change in any group. A novel observation wasthat of 30% increases in spectral linewidth in early HD at both timepoints (p<0.01).Conclusions Our data support patterns of higher MI levels and lowertNAA in early HD. The pattern of lower tNAA may begin inpremanifest HD. The lack of longitudinal metabolite change is notunusual over such a short duration of follow-up. We also identiﬁedfor the ﬁrst time, consistent increases in MRS spectral linewidth inearly HD.H07 PRIMARY SKIN FIBROBLAST CULTURES IN HUNTINGTON’SDISEASE RESEARCHdoi:10.1136/jnnp.2010.222653.7L Hasholt, S B Nielsen, N H Skotte, J E Nielsen, A Nørremølle. Section of Neuro-genetics, Department of Cellular and Molecular Medicine, University of Copenhagen,The Panum Institute, Copenhagen, DenmarkBackground Cultured skin ﬁbroblasts from HD patients seem to bean attractive model for in vitro studies of molecular pathology inHD, and in the hunt for HD biomarkers, as sampling is minimallyinvasive and the effect of the mutation can be studied in the correctgenetic background.Aims Here we discuss results gathered from the literature togetherwith some of our own unpublished results on HD patient ﬁbro-blasts.Outcome Although HD primary ﬁbroblast cultures have beenestablished and studied for a long time, results revealing charac-teristic phenotypic traits of this cell type are sparse. Many inves-tigations have focused on growth characteristics but no conclusioncould be drawn just as studies of cellular morphology so far haveyielded somewhat confounding results. There have been multipleexplanations suggested, including variations in growth character-istics of individual cell lines, which are also known from normalﬁbroblast cultures, and differences in culture conditions like theuse of different culture media, concentration of serum, addition ofantibiotics, surface of culture disc, etc, conditions which make itdifﬁcult to compare results obtained from different experimentalset-ups. Recently, examples of functional deﬁcits have been foundin HD ﬁbroblasts including vesicular trafﬁcking, lipid metabolismand proteasome inhibition as well as growth factor and enzymeactivity changes. Future investigations are needed to revealthe pathways involved and to show if they relate to changes inCNS.Conclusion Our considerations are useful for planning collection ofskin biopsies and multicentre studies on cultured ﬁbroblasts.J Neurol Neurosurg Psychiatry September 2010 Vol 81 Suppl 1 A35EHDN Plenary Meeting: abstracts group.bmj.com on October 29, 2012 - Published by jnnp.bmj.comDownloaded from doi: 10.1136/jnnp.2010.222653.5 2010 81: A35J Neurol Neurosurg Psychiatry E Marchina, A Bozzato, S Ferraboli, et al. Huntington's disease patients and controlsGene expression profile in fibroblasts of H05 http://jnnp.bmj.com/content/81/Suppl_1/A35.1Updated information and services can be found at: These include:serviceEmail alertingthe box at the top right corner of the online article.Receive free email alerts when new articles cite this article. Sign up inCollectionsTopic (1107 articles)Stroke    (1000 articles)Memory disorders (psychiatry)    (1349 articles)Drugs: CNS (not psychiatric)    (598 articles)Movement disorders (other than Parkinsons)    Articles on similar topics can be found in the following collectionsNotes http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to: http://journals.bmj.com/cgi/reprintformTo order reprints go to: http://group.bmj.com/subscribe/To subscribe to BMJ go to: group.bmj.com on October 29, 2012 - Published by jnnp.bmj.comDownloaded from 

Gene expression profile in fibroblasts of Huntington's disease patients and controls

Gene expression profile in fibroblasts of Huntington's disease patients and controls

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