Huntington’s disease is extraordinary for several reasons. It is caused by changes in a single gene – Huntingtin – and its mode of inheritance means that a child from a patient who has the disease has a 50% chance of being affected by it, too. Uncommonly for a genetic disease, the typical age when symptoms start to be experienced is in mid-adulthood, between 30 and 50 years old.
Huntington’s is classed as a neurodegenerative disease, which means that after onset, certain nerve cells are lost. The Huntingtin gene that is altered in the disease expresses a toxic protein – also called Huntingtin – in every cell of the body, but only a specific type of nerve cell (called medium spiny neurons) in a certain part of the brain (called the striatum) dies in Huntington’s patients.
When these nerve cells die, it causes patients to display the disease’s characteristic involuntary movements. Those with the illness typically experience a gradual decline in motor skills, cognitive abilities and behaviour over a 20 year period. It leads to them needing 24 hour nursing care, and ultimately the disease is fatal.
Most previous research into Huntington’s has focused on the course the disease takes after symptoms become apparent. But the Huntingtin protein is expressed in every cell from the earliest stages of embryonic development. So for our recently published study we wanted to better understand the effects of the mutant gene on brain cells before the onset of symptoms.
We chose to investigate the earliest ages at which behavioural tests can be performed – shortly after birth. We found that the mutant Huntingtin gene causes changes in mouse and rat pups long before the onset of “classical” symptoms (for example, involuntary movements).
We also discovered that the animals with Huntington’s have lower anxiety and show more risk-taking behaviour than their unaffected siblings. For ethical reasons, clinical studies involving juveniles or young adults affected by the Huntingtin mutation where symptoms have not yet appeared are very limited. Nevertheless, some study investigators reported anecdotally that these individuals showed more outgoing behaviour.
We were able to identify molecular and cellular changes that may explain these behavioural differences. For example, pathways used for communication between nerve cells that use a transmitter called dopamine were deregulated at several levels. This means that the recognition of this transmitter was lowered, compared to how it would have been if the mutant Huntingtin gene had not been present.
An early phase
When considering our findings together with reports from other research groups, it becomes apparent that Huntington’s disease has a previously unrecognised, early phase. During this stage – which ranges probably from development of an embryo to early adulthood – the body compensates for the changes caused by the mutant Huntingtin gene, so there are no disease-like symptoms.
In our study, we also tested a new drug called Panobinostat – which is being used in clinical trials for treatment of cancer. We found that it could completely restore the changes caused by Huntington’s disease. While this drug cannot alter the underlying mutation, it affects changes in gene expression that cause the altered behaviour. The mice we worked with showed less risk-taking behaviour after being treated with Panobinostat, for example. This is a promising step towards developing new therapies for Huntington’s, where the intention is to delay the onset of the disease.
Our research shows that the mutant Huntingtin gene causes changes on multiple levels, at an age range which has not been previously investigated. It affects gene and protein, nerve cells, and behaviour, too. The prodromal stages – before symptoms appear – in Huntington’s are a window of opportunity for therapies that aim to modify the course of the disease.
Currently, however, there is a lack of molecular markers – an indicator of the presence or severity of a disease – that allow researchers to monitor success of treatments. But we hope that our study provides a starting point to identify and refine such biomarkers, which in turn could be used to set up studies in other pre-symptomatic juvenile gene carriers, who could be treated and then monitored via blood gene expression and MRI scans.