Early white matter pathology in the fornix of the limbic system in Huntington disease

Sanaz Gabery,Rachel Y Cheong,Costanza Ferrari Bardile,Catriona Mclean,Åsa Petersén,Barbara Baldo,Mahmoud A Pouladi,Brendan Tan,Jing Eugene Kwa,Nellie Georgiou-Karistianis,Govinda R Poudel,Glenda Halliday

doi:10.1007/s00401-021-02362-8

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.

Highlights

Huntington disease (HD) is a fatal autosomal dominant disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene
The analysis revealed that differentially expressed genes (DEG) between HD and control cases are enriched for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2 (PRC2), as well as RE1 Regulation Transcription Factor (REST) (Fig. 4j)
white matter (WM) changes have emerged as important aspects of pathology in HD

Summary

Introduction

Huntington disease (HD) is a fatal autosomal dominant disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. Pouladi and Åsa Petersén shared last authors. The hypothalamus and the limbic system have been suggested to play a role for non-motor symptoms and signs of HD [6]. The hypothalamus has been shown to be affected more than a decade prior to the onset of clinical disease [1, 2], with pathological changes in the hypothalamus associated with the early non-motor features of HD [25, 26]. Other parts of the limbic system have been less studied in HD

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Conclusion