Tag: Huntington’s disease

Impact of HD Gene on Childhood IQ and Brain Growth

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by Jennifer Brown, University of Iowa

The genetic mutation that causes Huntington’s disease (HD)—a devastating brain disease that disrupts mobility and diminishes cognitive ability—may also enhance early brain development and play a role in promoting human intelligence.

This revelation comes from more than 10 years of brain imaging and brain function data, including motor, cognitive, and behavioral assessments, collected from a unique population—children and young adults who carry the gene for HD. While an HD mutation will eventually cause fatal brain disease in adulthood, the study finds that early in life, children with the HD mutation have bigger brains and higher IQ than children without the mutation.

“The finding suggests that early in life, the gene mutation is actually beneficial to brain development, but that early benefit later becomes a liability,” says Peg Nopoulos, MD, professor and head of psychiatry at the UI Carver College of Medicine, and senior author on the study published in The Annals of Neurology.

The finding may also have implications for developing effective treatments for HD. If the gene’s early action is beneficial, then simply aiming to knock out the gene might result in loss of the developmental benefit, too. Creating therapies that can disrupt the gene’s activity later in the patient’s lifetime might be more useful.

The new data about the gene’s positive effect on early brain development is also exciting to Nopoulos for another reason.

“We are very interested in the fact that this appears to be a gene that drives IQ,” she says. “No previous study has found any gene of significant effect on IQ, even though we know intelligence is heritable.”

HD gene linked to better brain development in early life

Huntington’s disease is caused by a mutation in the huntingtin (HTT) gene. The protein produced by the HTT gene is necessary for normal development, but variations within a segment of the protein have a profound effect on the brain.

The segment in question is a long repeat of one amino acid called glutamine. More repeats are associated with bigger, more complex brains. For example, species such as sea urchins or fish have no repeats, but these repeats start to appear higher up the evolutionary ladder. Rodents have a few repeats, while apes (our closest relatives) have even more repeats; and humans have the most.

Most people have repeats in the range of 10–26, but if a person has 40 or more repeats, then they develop HD. Although the gene expansion is present before birth, HD symptoms do not appear until middle age. Nopoulos’s team at the University of Iowa has a long history of studying how the HTT gene expansion affects brain development in the decades before disease onset.

“We know that the expanded gene causes a horrible degenerative disease later in life, but we also know it is a gene that is crucial for general development,” she says.

“We were surprised to find that it does have a positive effect on brain development early in life. Those who have the gene expansion have an enhanced brain with larger volumes of the cerebrum and higher IQ compared to those who don’t.”

In particular, the study found that decades before HD symptoms appeared, children with the HD gene expansion showed significantly better cognitive, behavioral, and motor scores compared to children with repeats within the normal range. Children with the expanded gene also had larger cerebral volumes and greater cortical surface area and folding. After this initial peak, a prolonged deterioration was seen in both brain function and structure.

The study gathered this data by following almost 200 participants in the Kids-HD study, the only longitudinal study of children and young adults at risk for HD due to having a parent or grandparent with the disease.

Evolutionary benefit comes at a cost

Although surprising, the findings are in line with studies by evolutionary biologists who believe that genes like HTT may have been “positively selected” for human brain evolution. This theory, known as antagonistic pleiotropy, suggests that certain genes can produce a beneficial effect early in life, but come at a cost later in life.

The finding also challenges the idea that the protein produced by the HD gene is solely a toxic protein that causes brain degeneration.

“Overall, our study suggests that we should rethink the notion of the toxic protein theory,” says Nopoulos, who is also a member of the Iowa Neuroscience Institute.

“Instead, we should consider the theory of antagonistic pleiotropy—a theory that suggests that genes like HTT build a better brain early in life, but the cost of the superior brain is that it isn’t built to last and may be prone to premature or accelerating aging.

“This means that instead of knocking down the gene for therapy, drugs that slow the aging process may be more effective.”

Next steps

Nopoulos’s team is already making progress extending the research from the Kids-HD program. Nopoulos has established the Children to Adult Neurodevelopment in Gene-Expanded Huntington’s Disease (ChANGE-HD), a multi-site study that aims to recruit hundreds of participants for a total of over 1,200 assessments to validate the key findings from the Kids-HD study and to enhance future research on HD.

A primary area of focus will be understanding how an enlarged brain can later lead to degeneration. One hypothesis Nopoulos and her team will explore involves the idea that an enlarged cortex might produce excess glutamate (an important neurotransmitter), which is beneficial in early brain development, but later leads to neurotoxicity and brain degeneration.

In addition to Nopoulos, the UI team included Mohit Neema, MD, UI research scientist and first author of the study; Jordan Schultz, PharmD; Douglas Langbehn, MD, Ph.D.; Amy Conrad, Ph.D.; Eric Epping, MD, Ph.D.; and Vincent Magnotta, Ph.D.

More information: Mohit Neema et al, Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy, Annals of Neurology (2024). DOI: 10.1002/ana.27046

Journal information: Annals of Neurology 

Provided by University of Iowa 

https://medicalxpress.com/news/2024-11-huntington-disease-gene-early-brain.html

Uncovering the early origins of Huntington’s disease

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Huntington’s neurons show multiple nuclei (blue) within the same cell, and other signs of trouble, long before symptoms emerge.

With new findings, scientists may be poised to break a long impasse in research on Huntington’s disease, a fatal hereditary disorder for which there is currently no treatment.

One in 10,000 Americans suffer from the disease, and most begin to show symptoms in middle age as they develop jerky movements—and as these patients increasingly lose brain neurons, they slide into dementia. But the new research suggests that these symptoms may be a late manifestation of a disease that originates much earlier, in the first steps of embryonic development.

A team at Rockefeller led by Ali Brivanlou, the Robert and Harriet Heilbrunn Professor, developed a system to model Huntington’s in human embryonic stem cells for the first time. In a report published in Development, they describe early abnormalities in the way Huntington’s neurons look, and how these cells form larger structures that had not previously been associated with the disease.

“Our research supports the idea that the first domino is pushed soon after fertilization,” Brivanlou says, “and that has consequences down the line. The final domino falls decades after birth, when the symptoms are observable.”

The findings have implications for how to best approach treating the disorder, and could ultimately lead to effective therapies.

A new tool

Huntington’s is one of the few diseases with a straightforward genetic culprit: One hundred percent of people with a mutated form of the Huntingtin (HTT) gene develop the disease. The mutation takes the form of extra DNA, and causes the gene to produce a longer-than-normal protein. The DNA itself appears in the form of a repeating sequence, and the more repeats there are, the earlier the disease sets in.

Research on Huntington’s has thus far relied heavily on animal models of the disease, and has left many key questions unanswered. For example, scientists have not been able to resolve what function the HTT gene serves normally, or how its mutation creates problems in the brain.

Suspecting that the disease works differently in humans, whose brains are much bigger and more complex than those of lab animals, Brivanlou, along with research associates Albert Ruzo and Gist Croft, developed a cell-based human system for their research. They used the gene editing technology CRISPR to engineer a series of human embryonic stem cell lines, which were identical apart from the number of DNA repeats that occurred at the ends of their HTT genes.

“We started seeing things that were completely unexpected,” says Brivanlou. “In cell lines with mutated HTT, we saw giant cells. It looked like a jungle of disorganization.”

When cells divide, they typically each retain one nuclei. However, some of these enlarged, mutated cells flaunted up to 12 nuclei—suggesting that neurogenesis, or the generation of new neurons, was affected. The disruption was directly proportional to how many repeats were present in the mutation: The more repeats there were, the more multinucleated neurons appeared.

“Our work adds to the evidence that there is an unrecognized developmental aspect to the pathology,” Brivanlou says. “Huntington’s may not be just a neurodegenerative disease, but also a neurodevelopmental disease.”

Toxic or essential?

Treatments for Huntington’s have typically focused on blocking the activity of the mutant HTT protein, the assumption being that the altered form of the protein was more active than normal, and therefore toxic to neurons. However, Brivanlou’s work shows that the brain disruption may actually be due to a lack of HTT protein activity.

To test its function, the researchers created cell lines that completely lacked the HTT protein. These cells turned out to be very similar to those with Huntington’s pathology, corroborating the idea that a lack of the protein—not an excess of it—is driving the disease.

The findings are significant, Brivanlou notes, since they indicate that existing treatments that were designed to block HTT activity may actually do more harm than good.

“We should rethink our approach to treating Huntington’s,” he says. “Both the role of the HTT protein and the timing of treatment need to be reconsidered; by the time a patient is displaying symptoms, it may be too late to medicate. We need to go back to the earliest events that trigger the chain reaction that ultimately results in disease so we can focus new therapies on the cause, not the consequences.”

The researchers hope their new cell lines will be a useful resource for studying the cellular and molecular intricacies of Huntington’s further, and suggest they may provide a model for examining other diseases of the brain that are specific to humans.

https://www.rockefeller.edu/news/21212-uncovering-early-origins-huntingtons-disease/

Huntington’s breakthrough may stop disease

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Prof Sarah Tabrizi , from the UCL Institute of Neurology, led the trials

By James Gallagher

The defect that causes the neurodegenerative disease Huntington’s has been corrected in patients for the first time, the BBC has learned. An experimental drug, injected into spinal fluid, safely lowered levels of toxic proteins in the brain. The research team, at University College London, say there is now hope the deadly disease can be stopped.

Experts say it could be the biggest breakthrough in neurodegenerative diseases for 50 years.

Huntington’s is one of the most devastating diseases. Some patients described it as Parkinson’s, Alzheimer’s and motor neurone disease rolled into one.

Peter Allen, 51, is in the early stages of Huntington’s and took part in the trial: “You end up in almost a vegetative state, it’s a horrible end.”

Huntington’s blights families. Peter has seen his mum Stephanie, uncle Keith and grandmother Olive die from it. Tests show his sister Sandy and brother Frank will develop the disease. The three siblings have eight children – all young adults, each of whom has a 50-50 chance of developing the disease.

The unstoppable death of brain cells in Huntington’s leaves patients in permanent decline, affecting their movement, behaviour, memory and ability to think clearly.

Peter, from Essex, told me: “It’s so difficult to have that degenerative thing in you.

“You know the last day was better than the next one’s going to be.”
Huntington’s generally affects people in their prime – in their 30s and 40s
Patients die around 10 to 20 years after symptoms start
About 8,500 people in the UK have Huntington’s and a further 25,000 will develop it when they are older

Huntington’s is caused by an error in a section of DNA called the huntingtin gene. Normally this contains the instructions for making a protein, called huntingtin, which is vital for brain development. But a genetic error corrupts the protein and turns it into a killer of brain cells.

The treatment is designed to silence the gene.

On the trial, 46 patients had the drug injected into the fluid that bathes the brain and spinal cord. The procedure was carried out at the Leonard Wolfson Experimental Neurology Centre at the National Hospital for Neurology and Neurosurgery in London. Doctors did not know what would happen. One fear was the injections could have caused fatal meningitis. But the first in-human trial showed the drug was safe, well tolerated by patients and crucially reduced the levels of huntingtin in the brain.

Prof Sarah Tabrizi, the lead researcher and director of the Huntington’s Disease Centre at UCL, told the BBC: “I’ve been seeing patients in clinic for nearly 20 years, I’ve seen many of my patients over that time die. For the first time we have the potential, we have the hope, of a therapy that one day may slow or prevent Huntington’s disease . This is of groundbreaking importance for patients and families.”

Doctors are not calling this a cure. They still need vital long-term data to show whether lowering levels of huntingtin will change the course of the disease. The animal research suggests it would. Some motor function even recovered in those experiments.

Peter, Sandy and Frank – as well as their partners Annie, Dermot and Hayley – have always promised their children they will not need to worry about Huntington’s as there will be a treatment in time for them. Peter told the BBC: “I’m the luckiest person in the world to be sitting here on the verge of having that. “Hopefully that will be made available to everybody, to my brothers and sisters and fundamentally my children.”

He, along with the other trial participants, can continue taking the drug as part of the next wave of trials. They will set out to show whether the disease can be slowed, and ultimately prevented, by treating Huntington’s disease carriers before they develop any symptoms.

Prof John Hardy, who was awarded the Breakthrough Prize for his work on Alzheimer’s, told the BBC: “I really think this is, potentially, the biggest breakthrough in neurodegenerative disease in the past 50 years. That sounds like hyperbole – in a year I might be embarrassed by saying that – but that’s how I feel at the moment.”

The UCL scientist, who was not involved in the research, says the same approach might be possible in other neurodegenerative diseases that feature the build-up of toxic proteins in the brain. The protein synuclein is implicated in Parkinson’s while amyloid and tau seem to have a role in dementias.

Off the back of this research, trials are planned using gene-silencing to lower the levels of tau.

Prof Giovanna Mallucci, who discovered the first chemical to prevent the death of brain tissue in any neurodegenerative disease, said the trial was a “tremendous step forward” for patients and there was now “real room for optimism”.

But Prof Mallucci, who is the associate director of UK Dementia Research Institute at the University of Cambridge, cautioned it was still a big leap to expect gene-silencing to work in other neurodegenerative diseases.

She told the BBC: “The case for these is not as clear-cut as for Huntington’s disease, they are more complex and less well understood. But the principle that a gene, any gene affecting disease progression and susceptibility, can be safely modified in this way in humans is very exciting and builds momentum and confidence in pursuing these avenues for potential treatments.”

The full details of the trial will be presented to scientists and published next year.

The therapy was developed by Ionis Pharmaceuticals, which said the drug had “substantially exceeded” expectations, and the licence has now been sold to Roche.

http://www.bbc.com/news/health-42308341