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Brain regions showing white matter loss in Huntington's Disease are enriched for synaptic and metabolic genes
McColgan, Peter Gregory, Sarah Seunarine, Kiran K. Razi, Adeel Papoutsi, Marina Johnson, Eileanoir B. Dürr, Alexandra Roos, Raymund Leavitt, Blair R. Holmans, Peter
McColgan, Peter
Gregory, Sarah
Seunarine, Kiran K.
Razi, Adeel
Papoutsi, Marina
Johnson, Eileanoir B.
Dürr, Alexandra
Roos, Raymund
Leavitt, Blair R.
Holmans, Peter
Author
McColgan, Peter
Gregory, Sarah
Seunarine, Kiran K.
Razi, Adeel
Papoutsi, Marina
Johnson, Eileanoir B.
Dürr, Alexandra
Roos, Raymund
Leavitt, Blair R.
Holmans, Peter
Scahill, Rachael I.
Clark, Chris A.
Rees, Geraint
Tabrizi, Sarah J.
Coleman, A.
Decolongon, J.
Fan, M.
Petkau, T.
Jauffret, C.
Justo, D.
Lehericy, S.
Nigaud, K.
Valabrègue, R.
Schoonderbeek, A.
’t Hart, E. P.
Hensman Moss, D. J.
Ghosh, R.
Crawford, H.
Papoutsi, M.
Berna, C.
Mahaleskshmi, D.
Reilmann, R.
Weber, N.
Labuschagne, I.
Stout, J.
Landwehrmeyer, B.
Orth, M.
Mayer, I.
Johnson, H.
Crawfurd, D.
Gregory, Sarah
Seunarine, Kiran K.
Razi, Adeel
Papoutsi, Marina
Johnson, Eileanoir B.
Dürr, Alexandra
Roos, Raymund
Leavitt, Blair R.
Holmans, Peter
Scahill, Rachael I.
Clark, Chris A.
Rees, Geraint
Tabrizi, Sarah J.
Coleman, A.
Decolongon, J.
Fan, M.
Petkau, T.
Jauffret, C.
Justo, D.
Lehericy, S.
Nigaud, K.
Valabrègue, R.
Schoonderbeek, A.
’t Hart, E. P.
Hensman Moss, D. J.
Ghosh, R.
Crawford, H.
Papoutsi, M.
Berna, C.
Mahaleskshmi, D.
Reilmann, R.
Weber, N.
Labuschagne, I.
Stout, J.
Landwehrmeyer, B.
Orth, M.
Mayer, I.
Johnson, H.
Crawfurd, D.
Abstract
Background
The earliest white matter changes in Huntington’s disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability.
Methods
Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington’s disease relative to control participants. The baseline cohort included 72 premanifest Huntington’s disease participants and 85 healthy control participants.
Results
We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington’s disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington’s disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles.
Conclusions
These findings suggest a dual mechanism of white matter vulnerability in Huntington’s disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss.
Keywords
connectome, genetics, Huntington’s Disease, imaging, transcription, white matter
Date
2018
Type
Journal article
Journal
Biological Psychiatry
Book
Volume
83
Issue
5
Page Range
456-465
Article Number
ACU Department
School of Behavioural and Health Sciences
Faculty of Health Sciences
Faculty of Health Sciences
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY 4.0
File Access
Open