Decoding Presymptomatic white matter changes in Huntington Disease (WIN-HD)

Lead Research Organisation: University College London
Department Name: Institute of Neurology


Huntington disease (HD) is an inherited neurodegenerative disease caused by a single mutation in the huntingtin gene. Onset occurs in adults, with slow progression and a combination of motor signs and cognitive changes, including dementia, as a result of underlying neurodegeneration of brain tissue. The mutation is an expansion of a CAG sequence within the gene and the length of the expansion has a strong effect on disease onset and course.

Early postmortem and imaging studies in HD have focused on grey matter changes in the subcortical brain structures such as the caudate and putamen. However, there is increasing recognition that white matter changes also play a role in the disease from the very early stages, many years before any clinical signs are evident. The exact nature of these white matter changes are not fully understood. Most imaging techniques used to date do not have the power to determine the specific mechanisms underlying white matter degeneration. For example, loss of white matter integrity may be due to degeneration of the axonal section of the neurone, or a reduction in the amount of myelin surrounding it. Myelin is produced by oligodendrocytes and it is thought that dysfunction within these cells may play an important role in the underlying neuropathology in HD.

We aim to improve our understanding of the role of oligodendrocytes in the white matter degeneration which typifies HD by:
a) examining white matter changes in individuals who carry the HD mutation but are not yet affected by the symptoms using advanced neuroimaging techniques
b) using mouse models of HD to examine disease-related changes in living animals (using imaging) and in postmortem brain tissue
c) examining postmortem human brain tissue to understand the nature of white matter changes in terms of characteristics such as axonal loss, demyelination and numbers of oligodendrocytes
d) determining whether other genes which cause dysfunction in oligodendrocytes have an impact on the disease course in HD mouse models

Technical Summary

Our working hypothesis is that oligodendrocyte alterations underlie and exacerbate neurodegeneration in HD. Using new techniques of imaging, neuropathology, cell biology, and genetics, WIN-HD will investigate prodromal white-matter changes in HD patients (22 available human brain tissues and 30 premanifest carriers and 30 gene negative controls for imaging studies) and in mice model. We will use an HD knock-in rodent model and models expressing oligodendrocytes modifiers.

We will test the hypothesis that white-matter changes exacerbate the pathogenic cascade in Huntington Disease (HD) characterized by motor and cognitive signs. These changes may include (1) perturbed axon-glia interactions, (2) loss of oligodendroglial functions, and (3) demyelination. The proposal originates from surprising findings: (1) white-matter atrophy occurs far earlier than clinical onset in HD; and (2) extensive white-matter changes are present in mouse models; and (3) expression of the HD-causing protein in oligodendrocytes may contribute to disease progression in mice. For this project, we have assembled experts in the human disorder, in HD rodent models, in human and animal brain imaging and in the molecular and cellular biology of myelination. Together, we will examine white-matter changes well before the onset of disease signs and look for parallel changes in human and rodent models. We will use diffusion-weighted spectroscopy combined with diffusion tensor imaging to distinguish between axonal and glial contribution to white matter changes. Using genetic tools in mice, we will determine the effects of altered oligodendrocyte function on disease progression. Our two-year program will allow us to infer whether neuroprotective therapies should focus on molecular targets that primarily function in oligodendrocytes.

Planned Impact

Huntington's disease (HD) patients and families, scientists and clinicians working on HD will all be beneficiaries of this research, as well as biotechnology and pharmaceutical companies with research and development and/or commercial interests in these areas. Improving our understanding of the disease-related degeneration of white matter in HD could be an important step forward in developing disease modifying treatments. A number of pharmaceutical and biotechnology companies have existing interests in Huntington's disease, not least because of its genetic and fully penetrant nature make it highly useful in understanding more common neurodegenerative disorders with which its shares many features, such as Alzheimer's disease and Parkinson's disease. Understanding the underlying cellular mechanisms of pathogenesis and seeking to identify new therapeutic targets can only help those endeavours.
The economic and societal burden of neurodegenerative disease is considerable and is certain to increase. Huntington's disease itself affects entire families, with the loss of health in affected individuals having life-changing implications for them, their families and carers. Children in HD families, who themselves may be carrying the disease-causing genetic mutation, may be particularly affected. Furthering our understanding of the pathogenesis of HD will eventually lead to useful disease-modifying treatments. Significant advances in research bring hope to family members and encourage participation in clinical trials.

To maximise the potential gain from our research findings, we will encourage data sharing prior to publication through academic collaboration. Conferences and meetings will help to foster new academic collaborations in addition to those that already exist or have been newly formed as part of this proposal. We plan to hold collaborative review meetings on a regular basis to monitor project progress and identify common themes in neurodegenerative disease research. Our groups benefit from close links with other researchers in their host departments and institutions, and by encouraging greater synergy between groups working on different disorders we hope to identify common mechanisms and means of targeting inflammation in neurodegeneration.


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Description WIN-HD collaboration with Paris 
Organisation Pitié-Salpêtrière Hospital
Country France 
Sector Hospitals 
PI Contribution Participant recruitment, analysis and scientific input on study results and dissemination
Collaborator Contribution Leadership of the project, participant recruitment, analysis and scientific input on study results and dissemination
Impact No output as yet as we are still in data collection phase
Start Year 2016