Huntingtin and brain development

In April of 2013 the CHDI Foundation will host its 8th Annual Therapeutics conference, this time in beautiful Venice, Italy. I will be chairing a session entitled ‘from the beginning: what developmental systems tell us about HD’, together with Dr. Elena Cattaneo, who is one of the HD scientists working, among other things, in understanding the role in development of the Huntingtin gene. HD is typically defined as a degenerative disorder; that’s a disorder in which the brain degenerates, while it is thought that its development is normal. This view, however, might need a revision. As a developmental biologist, I always thought of HD as a disease of development; with no evidence for it, simply based on intuition. However, several facts suggest that I might not have been wrong. The reality is that in mice, normal huntingtin is needed for development of the embryo, and particularly for the proper emergence of the forebrain. However, the precise role of Huntingtin in development is still unclear. It is my belief that understanding this function – the first known function of huntingtin- will be important in elucidating the mechanisms by which mutant huntingtin causes disease … in adulthood.

It is a curious finding that many of the genes which cause degenerative diseases of the brain (and other organs, such as the pancreas in diabetes) are embryonically important genes. However, their function in development has not been well studied, and mostly because of a simple fact: these diseases are thought to occur from a ‘gain of function’, ‘toxic’ activity of the mutated proteins, and not a loss of function (the findings that implicate them in developmental processes). Therefore, if the diseases are caused by toxic ‘new activities of the mutant proteins’, why bother to study the role when the protein is not there?

Well, because the ‘mutated protein’ is likely doing something that the ‘normal protein’ does, and by inference the effects of the mutation somehow alter a function/s normally associated with the function of the gene in the absence of disease. So in order to understand what goes wrong, we need to understand what happens normally in the ‘huntingtin world’ – this is where developmental systems come in handy, as this is the ‘context’ in which Huntingtin is most needed.

During the TRACK HD longitudinal studies, researchers Sarah Tabrizi and colleagues imaged the brains of people at risk for HD, to understand the evolution of the ‘degeneration’, and to see whether we could predict when the carriers would manifest clinical disease. They surprisingly discovered that even 10-15 years prior to any clinical manifestation of HD, affected carriers had significant degeneration of the brain regions lost to HD. So how far does this process go? Is it possible that people start off this way? Or how early does the disease start killing brain cells? Another scientist, Peggy Nopoulos from the University of Iowa, and colleagues, has gone back to children at risk for HD and to study juvenile HD cases. There are already abnormalities in their brains, which suggest that it is very likely their brains develop abnormally in the first place. Remember in humans (as opposed to rodents), brain development continues through childhood – into adolescence. So a developmental function for Huntingtin could well explain the early effects of the disease, well before clinical symptoms emerge. Furthermore, in mice expressing mutant Huntingtin with large CAG repeats, there is also evidence of subtle –but observable- brain development abnormalities.

It is tempting to propose that Huntingtin mutation carriers have an abnormal brain development process that predisposes some parts of their brains to degenerate later on. This theory might explain something else in HD– the inherent variability in the spectrum of clinical symptoms. Small alterations during critical developmental windows in the brain regions affected by HD might have varied and profound consequences – in the number of cells that develop, the types of cells, in their connections with other cells, or in the wiring between different brain regions. This can directly affect how information is processed, perhaps explaining why the same mutation can give rise to very different medical problems.

Interestingly, the degree of regional brain size in childhood is also correlated with the length of the longest CAG Huntingtin allele (one of the 2 copies of the gene)– including in the normal subjects studied (although these numbers are small, the data point in this direction). It is almost as if the size of the brain (which might be associated with improved cognition for instance) might be influenced by the CAG repeat length, which might explain why during evolution Huntingtin versions have been selected for longer repeats – a good thing if it weren’t for the fact, that after a certain length of the repeat, HD develops with age.

All these facts make understanding development of the brain in the context of HD very important. The good news is that in spite of having brain differences that can be observed 20 years before clinical symptoms, the symptoms are not present, so we have plenty of time to intervene. The bad news is that the way we think about the disease might be significantly changed given this potential developmental trajectory.

Because of these reasons, several scientists have now derived human embryonic stem cells from HD subjects- and they are making neurons from these cells, so that we can study what normal and mutant Huntingtin does in the cells that eventually die from the disease. Given the critical role of Huntingtin in embryonic development, and the usefulness of developmental systems to identify signaling mechanisms, it is likely that by studying these patient-derived stem cells we will gain much insight into the disease. This is the topic of the session I will chair in Venice on April 10, 2013, and I will be joined by 3 great developmental neurobiologists: Steve Goldman (Rochester), Jeff Macklis (Harvard) and Ali Brivanlou (Rockefeller University). I will let you know how it goes later – but remember, how we develop is probably more important that we think!