Huntington’s Alters Brain Development Before Birth, Study Shows

Huntington’s disease alters nerve cell development in the cortex — a brain region largely affected in people with the condition — before birth, a study has found.

“Huntington’s definitely has a neurodevelopmental component in addition to a neurodegenerative disease,” Sandrine Humbert, PhD, the study’s senior author at the Grenoble Institut des Neurosciences, in France, said in a news story.

This discovery may have important implications on the nature and timing of future treatments for patients. It also opens the door to potential research into understanding how these early neuronal defects contribute to neurodegeneration later in life, which may help scientists identify new biomarkers and therapeutic targets.

The study, “Huntington’s disease alters human neurodevelopment,” was published in the journal Science.

Huntington’s disease is caused by excessive (more than 36) repeats of a portion of DNA, called CAG triplets within the HTT gene. This results in the production of an abnormal and toxic version of the huntingtin protein (mHTT).

Huntington’s symptoms result from a degeneration of certain brain regions, including the cortex — the outer layer of the brain that controls thought, behavior, and memory — and the striatum, which is involved in motor function and cognition.

While researchers have long believed that Huntington’s involved normal brain development followed by a degenerative phase, during which symptoms appear, increasing evidence suggests that the disease may also affect prenatal neurodevelopment.

Studies in mouse models of the disease have shown that mHTT interferes with brain development, resulting in a thinner cortex, and that early exposure to mHTT is sufficient to trigger Huntington’s features when mice reach adulthood.

Moreover, mHTT has been shown to lead to premature nerve cell maturation and fewer neural progenitor cells (those that can give rise to several types of nerve cells) in human brain tissue grown in the lab. Additionally, presymptomatic children were found to have smaller brains and striatum abnormalities long before symptoms appeared.

Now, researchers led by Humbert and Alexandra Durr, MD, PhD, of the Paris Brain Institute have shown for the first time that Huntington’s leads to changes in brain development as early as the prenatal stages. Durr is also a professor at Sorbonne University, in Paris.

The team analyzed cortex tissue from eight 13-week-old human fetuses donated by parents following medical terminations of pregnancy: four genetically diagnosed with Huntington’s (about 40 CAG repeats) and four without the disease.

At this stage of development, cortical neurons — which will connect to the striatum and degenerate in Huntington’s decades later — are created from progenitor cells at a cortical region called the ventricular zone.

Results showed that compared with healthy fetuses, progenitor cells from Huntington’s carrier fetuses presented several defects, including an abnormal localization of mHTT and proteins involved in keeping progenitor cells together, impaired intracellular transport, and defects in primary cilia, small tubular structures essential to their function.

All these abnormalities disrupted the “division-maturation” balance of the progenitor cells, leading to a premature maturation into nerve cells at the expense of the pool of dividing cells that provide new progenitor cells.

Notably, these neural progenitor defects were observed even in fetuses with relatively fewer CAG repeats that would typically cause later disease onset.

“Thirteen weeks gestation is the time point when you need a lot of cells to be generated,” said Humbert, who is also the research director of INSERM (the French National Institute for Health and Medical Research).

“The implications for the fetal brain with [a Huntington’s disease] mutation is that there is a shift to [maturate] early and, as a result, you generate fewer neurons, at least at this specific time point during development,” she added.

Similar abnormalities were also observed in a mouse model of the disease at an equivalent stage of development, validating this animal model for future studies that may evaluate the underlying mechanisms of the disease at other stages of prenatal development or after birth.

“This is the first time that abnormalities of brain development have been identified in this disease. Abnormalities which are also relatively large and extensive, although we are not yet able to determine their direct consequences,” Humbert and Durr said in a separate INSERM press release.

Regarding the absence of symptoms in Huntington’s patients until later in life, the two researchers hypothesized that the brain may implement, very early on, compensatory mechanisms for these neurodevelopmental changes, allowing normal functioning.

“It could be the same in people who carry mutations linked to other types of degeneration, such as Alzheimer’s disease or amyotrophic lateral sclerosis,” they added.

Humbert also said that once disease-modifying therapies for Huntington’s are developed, “we should treat as early as possible or differently in pre-manifest compared to symptomatic stages of the disease, or it may not be sufficient.”

Sarah Tabrizi, MD, PhD, a professor of clinical neurology at University College London Institute of Neurology and who was not involved in the study, said that these findings mean “that there is still great potential for therapies to potentially prevent the neurodegeneration occurring if we treat early enough. We need to understand more about the very earliest manifestations of neurodegeneration and then intervene at the optimal stage.”

The researchers will continue to characterize the brain development of mouse models of the disease, and focus on how these early defects contribute to the disease in adults and how compensation for these defects could be regulated during the symptom-free period.