By Jamie Talan August 20, 2020 The Science Explained Article In Brief

Scientists identified several cellular abnormalities in the developing cortex from fetal tissues carrying the mutant gene implicated in Huntington's disease. The findings suggest that the disease alters human development at an early age.

Teams of French researchers have found cellular changes that alter cortical development in the brains of human fetuses who carry the mutant huntingtin gene (mHTT) implicated in Huntington's disease (HD).

The finding adds a new wrinkle to the puzzle of HD as many people who carry the mutation can live healthy lives for four decades or longer before the onset of symptoms.

No one knows why, but this is a common thread in other late-onset genetically-driven neurodegenerative conditions like Alzheimer's and Parkinson's disease, the researchers said. And a growing number of researchers believe that it is best to treat people with the HD mutation as early as possible.Now, findings from this study, published online July 16 in Science, beg the question: How early?

The researchers, led by Sandrine Humbert, PhD, research director of INSERM (the French National Institute for Health and Medical Research) and group leader at the Grenoble Institut des Neurosciences, and Alexandra Durr, MD, PhD, professor at Sorbonne University and team leader of the Paris Brain Institute at Pitie-Salptrire Hospital, had access to fetal tissue from families that terminated their pregnancy in the context of a prenatal test. The developing fetus carried the mHTT.

Other mouse and neuroimaging studies with pre-manifest mutation carriers have suggested that the mutation might affect neurodevelopment but this is the first time that scientists have looked to the human fetus to know for sure.

Dr. Durr works with people undergoing genetic testing and counseling for Huntington's disease. Her team was able to collect cortical tissue from four HD mutation carriers when the pregnancies were terminated at around 13-weeks' gestation and tissue from four healthy controls.

This age is an opportune time to assess the tissue, the study authors noted, because at this stage the cortical neurons that project to the striatumthose that become dysfunctional and die during the course of the diseaseare being born from progenitor cells at the ventricular zone.

Thirteen weeks gestation is the time point when you need a lot of cells to be generated, Dr. Humbert explained. At this stage in development cells are massively cycling. The implications for the fetal brain with an HD mutation is that there is a shift to differentiate early and, as a result, you generate fewer neurons, at least at this specific time point during development.

The scientists identified several cellular abnormalities in the developing cortex, including mislocalization of the mutant huntingtin protein and other junction proteins that keep the neuroepithelium sealed. They observed abnormal ciliogenesis and changes in mitosis and cell-cycle progression, which correlated with defects in the balance between renewal and differentiation of progenitors.

In neuroprogenitor cells, this balance is tightly regulated to provide the right amount of neurons along the development of the cortex. Fewer proliferating cells and more progenitors prematurely began to differentiate in the tissues of HD carrierssubtle findings that are changing the landscape of the cortex.

Huntington's definitely has a neurodevelopmental component in addition to a neurodegenerative disease, Dr. Humbert explained. Studies in mice have found similar cellular abnormalities.

These data are supported by similar findings in mice that show mutant HTT impairs neuroprogenitor cell division, migration, and maturation, and that these changes result in a thinner cortex. Additional studies have revealed that early exposure to mutant HTT is enough to trigger signs of HD when the mice grow up. Neuroimaging studies with pre-symptomatic mutation carriers, even children, have shown smaller intracranial volume in HD mutation carriers.

What is also intriguing is that these events occurred even though the fetuses had small pathological expansions39, 40, and 42 repeats that would typically cause an adult onset of HD.

The findings trigger a number of questions: Why aren't there any obvious clinical problems until mid-life? Do these early developmental changes set the stage for symptoms decades down the road? Are other brain cells compensating for the changes and it takes 40-plus years for symptoms to develop?

Dr. Humbert and her colleagues said that the defects we observed likely render the cortico-striatal circuitry more vulnerable to the later dysfunctions characteristic of HD. The path to degeneration is complex, however, and weaves together both pathogenic and compensatory mechanisms.

They cited a recent pair of studies in Neurology by Peg Nopoulos, MD, and her colleagues at the University of Iowa, Carver College of Medicine that looked at children who are HD mutation carriers. They showed initial striatal enlargement with hyper-connectivity between the striatum and the cerebellum. Over time, the striatum decreases and the connections weaken. Although the cerebellar connections initially may help compensate for the abnormally developed striatum, it is the loss of these connections that may ultimately lead to motor abnormalities. Again, it will be decades before any obvious motor signs develop.

Once there are disease-modifying therapies, we know 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, said Dr. Humbert.

She said she is now interested in understanding how these early defects contribute to adult pathology, and how their compensation could be regulated during the silent symptom-free period. This should give access to new molecules of interest, either as treatments or biomarkers, she added.

It is a beautiful paper, said Christopher A. Ross, MD, PhD, director of neurobiology and professor of psychiatry and behavioral sciences at Johns Hopkins Medicine. The concept fits with ideas people have had. Their study is groundbreaking.

It's unclear how these cell-cycle abnormalities alter normal development, said Dr. Ross. I have been doing pre-manifest genetic testing for years, and my belief is that asymptomatic people who are far from their predicted onset but test positive are clinically completely normal.

These data are very interesting, said Sarah Tabrizi, MD, PhD, professor of clinical neurology at University College London Institute of Neurology. There has been debate in the HD field regarding the existence of a neurodevelopmental deficit, and evidence is accruing that this may be the case based on differentiating HD induced pluripotent stem cell systems, mouse development, and now these studies of early human development.

We recently found that HD gene carriers ~24 years before predicted disease onset had essentially completely normal brains including normal cortico-striatal connectivity on advanced neuroimaging, apart from a slightly smaller striatum, which we hypothesized resulted in selective vulnerability of the striatum to subsequent neurodegeneration in HD (Lancet Neurology 2020). Importantly, our HD gene carriers performed as well as matched controls on a range of stringent cognitive and motor assessments.

This all suggests that we need to treat as early as possible with disease-modifying therapies to enable us to delay or prevent symptom onset, Dr. Tabrizi said, and means 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.

Dr. Ross believes that the brain figures out a workaround of these developmental alterations but agrees that it may leave the brain more vulnerable later in life. He added, These findings are conceptually very important, though not necessarily with immediate implications for patients or those who are asymptomatic but test positive.

He said that this finding represents a paradigm shift that will lead scientists to look for developmental abnormalities in other neurodegenerative diseases.

It is important to emphasize how the Huntington gene (HTT) affects the brain in the context of a lifetime trajectory, added Dr. Nopoulos, the Paul W. Penningroth professor of psychiatry and chair in the department of psychiatry at University of Iowa Carver College of Medicine. This gene is vital for brain development. Our group has shown that HTT drives brain development and that repeats in HTT are beneficial, and the higher the repeat, the higher the IQ. For individuals with repeats in the range of 39-42, like those in the fetal tissue study, HTT likely contributed to the development of a cerebellar-striatal-cortical circuit that was initially advantageous (which is why they are found to be asymptomatic in the Tabrizi study), but later in life, vulnerable to degeneration. Therefore, although the findings in the fetal tissue study are reported as abnormalities, they are more likely to be evidence of differences since the changes are not pathologic until much later in life.

However, she added, everything about HTT is on a spectrumthe classic dose effect of repeats on the age of onset is a good example where greater repeats result in earlier onset. The same is likely true for development.

Human brain development is prolonged, lasting until roughly age 30, she continued. Those with repeats in the low mutant range (36-42) will have a chance for full brain development before the vulnerable cerebellar-striatal-cortical circuit begins to degenerate and disease manifests. However, in those with longer repeats (above 50), the vulnerable brain circuit may begin to degenerate before full brain maturation is complete.

In this range of repeats, the ultimate effect of mHTT on brain development may be detrimental. These considerations are vitally important when considering when to intervene with preventive therapies such as gene knock-down drugs. In those with low mutant repeats, knocking down the gene early in life (before age 30) may be detrimental to brain development, yet in those with high repeats, rescue may need to be much earlier (adolescence).

Drs. Humbert, Durr, Ross, and Nopoulos had no relevant disclosures.

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