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Early white matter pathology in the fornix of the limbic system in Huntington disease
Gabery, Sanaz Kwa, Jlng Cheong, Rachel Y. Baldo, Barbara Bardile, Costanza Ferrari Tan, Brendan Mclean, Catriona Georgiou-Karistianis, Nellie Poudel, Govinda R. Halliday, Glenda
Gabery, Sanaz
Kwa, Jlng
Cheong, Rachel Y.
Baldo, Barbara
Bardile, Costanza Ferrari
Tan, Brendan
Mclean, Catriona
Georgiou-Karistianis, Nellie
Poudel, Govinda R.
Halliday, Glenda
Abstract
Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, the fornix, is affected in HD. We demonstrate that the fornix is 34% smaller already in prodromal HD and 41% smaller in manifest HD compared to controls using volumetric analyses of MRI of the IMAGE-HD study. In post-mortem fornix tissue from HD cases, we confirm the smaller fornix volume in HD which is accompanied by signs of myelin breakdown and reduced levels of the transcription factor myelin regulating factor but detect no loss of oligodendrocytes. Further analyses using RNA-sequencing demonstrate downregulation of oligodendrocyte identity markers in the fornix of HD cases. Analysis of differentially expressed genes based on transcription-factor/target-gene interactions also revealed enrichment for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2, as well as RE1 Regulation Transcription Factor. Taken together, our data show that there is early white matter pathology of the fornix in the limbic system in HD likely due to a combination of reduction in oligodendrocyte genes and myelin break down.
Keywords
huntingtin, oligodendrocyte, fornix, MRi, RNA sequencing
Date
2021
Type
Journal article
Journal
Acta Neuropathologica
Book
Volume
142
Issue
Page Range
781-806
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY 4.0
File Access
Open