Devastating neurodegenerative diseases such as Huntington’s,Alzheimers and Parkinson’s are all associated with protein deposits in the brain, known as amyloid. Despite the massive investment in research into the cause and toxicity of amyloids, deciphering the first step in forming along with effective therapies has remained elusive.
For the first time, scientists at the Stowers Institute for Medical Research have discovered the structure of the first step in training of amyloid , called the nucleus, for Huntington’s disease. Study from the laboratory of research associate Randal Halfmann, Ph.D., proposes a radical new method for treating not only Huntington’s disease but potentially dozens of other amyloid-associated diseases by preventing the initial rate-limiting switch from occurring .
The results of research have been posted on eLife.
Huntington’s disease – that’s what its beginning is
“This is the first time anyone has experimentally determined the structure of an amyloid core, even though most major neurodegenerative diseases are associated with amyloids,” Halfmann said. “One of the great mysteries of Huntington’s, Alzheimer’s and ALS is why the disease coincides with amyloid, but the amyloids themselves are not the main culprits.”
Co-first authors Tej Kandola, Ph.D., and Shriram Venkatesan, Ph.D., uniquely identified the structure of the amyloid core for huntingtin, the protein responsible for Huntington’s disease, finding that the core is form within a single protein molecule.
Proteins are the cell’s workers built from unique sequences of 20 amino acids, their building blocks. Some proteins have repeats of one of these amino acids: glutamine (Q for short). Huntington’s disease and eight other diseases, collectively called “PolyQ diseases,” occur when certain proteins have too long a repeat. Somehow, this causes the proteins to fold into a specific structure which starts a chain reaction that kills the cell.
“For three decades, we’ve known that Huntington’s disease and related life-threatening diseases occur when proteins contain more than about 36 Q in a row, causing protein chains to form in the brain, but we didn’t know why.” Halfman said. . “Now we understand what the first link in the chain looks like, and in doing so, we’ve discovered a new way to stop it.”
“I am, frankly, amazed that such an intuitive physical model of nucleation has emerged despite the inherent complexity of the cellular environment,” said Professor Jeremy Schmit, Ph.D., of Kansas State University. “I’m really excited about the insight and testable hypotheses this work inspires.”
These new findings are potentially a paradigm shift for how we view amyloids. The results of this research suggest that it is the busy early stages of amyloid formation, just after nucleus formation, that cause neuronal cell death.
In addition to uncovering the key structure that initiates the formation of polyQ amyloid, the researchers discovered that it is only formed in isolated molecules of the protein. The clumping of the proteins in the cells prevented the formation of amyloids altogether. This is a new therapeutic avenue that the team plans to explore further in mice and brain organoids.
A technique recently developed by the Halfmann Lab, Distributed Amphifluoric Förster Resonance Energy Transfer (DAmFRET), shows how a protein self-assembles in single cells. This method proved to be crucial for observing the nucleation event that limits the rate of amyloid formation.
“A key innovation has been to minimize the volume of the reaction to such an extent that we can witness its stochasticity, or randomness, and then modify the sequence to understand what governs it,” Halfmann said.
Designing and testing specific models of Q allowed the team to infer the minimal structure that amyloid could form, a bundle of four strands each with three Qs at specific locations. This tiny crystal within a single protein molecule is the first step in a chain reaction that causes disease.
“Previous test-tube work supports a monomeric core, but this model has been controversial,” Halfmann said. “We now have strong evidence that 36Q is the critical number for nucleation to occur in individual protein molecules and, moreover, that this is how it occurs within living cells.”
In essence, this work provides a molecular model to study the structure of any amyloid nucleus. Furthermore, the correlation between aging and amyloids suggests that this method could ultimately uncover the molecular mechanisms that cause ageing. The preventive approach to eliminate or at least delay nucleation offers hope for people with pathological PolyQ proteins.
“The emerging paradigm is that everything follows from a single event, a spontaneous change in the shape of proteins,” Halfmann said. “That event ignites the chain reaction for cell-killing amyloids and may provide critical insight into how amyloids cause disease.”
Huntington’s disease is a rare inherited disorder that causes the progressive breakdown (degeneration) of nerve cells in the brain. Huntington’s disease has a large impact on a person’s functional abilities and usually results in movement, thinking (cognitive), and psychiatric disorders.
Symptoms of Huntington’s disease can develop at any time but often first appear when people are in their 30s or 40s. If the condition develops before the age of 20, it is called juvenile Huntington’s disease. When Huntington’s develops early, the symptoms are somewhat different and the disease can progress more quickly.
Medications are available to help manage the symptoms of Huntington’s disease. But treatments cannot prevent the physical, mental and behavioral decline associated with the condition.
Huntington’s disease usually causes movement, cognition, and psychiatric disorders with a broad spectrum of signs and symptoms. Which symptoms appear first varies greatly from person to person. Some symptoms appear more dominant or have a greater effect on functional ability, but this can change over the course of the disease.
Movement disorders associated with Huntington’s disease can include both involuntary movement problems and impairments in voluntary movements, such as:
Involuntary jerking or writhing movements (chorea)
Muscle problems, such as muscle stiffness or contracture (dystonia)
Slow or unusual eye movements
Impaired gait, posture and balance
Difficulty speaking or swallowing
Impairments in voluntary, rather than involuntary, movement can have a greater impact on a person’s ability to work, perform daily activities, communicate and remain independent.
Cognitive impairments often associated with Huntington’s disease include:
Difficulty organizing, prioritizing, or focusing on tasks
Lack of flexibility or a tendency to get stuck in a thought, behavior, or action (perseverance)
Lack of impulse control which can lead to outbursts, acting without thinking, and sexual promiscuity
Lack of awareness of one’s own behaviors and abilities
Slowness in processing thoughts or “finding” words
Difficulty learning new information
The most common psychiatric disorder associated with Huntington’s disease is depression. This is not simply a reaction to receiving a Huntington’s disease diagnosis. Instead, depression appears to occur due to injury to the brain and subsequent changes in brain function. Signs and symptoms may include:
Feelings of irritability, sadness or apathy
Fatigue and loss of energy
Frequent thoughts of death, death, or suicide
Other common psychiatric disorders include:
obsessive-compulsive disorder, a condition characterized by recurring, intrusive thoughts and repetitive behaviors
Mania, which can cause elevated mood, hyperactivity, impulsive behavior, and inflated self-esteem
Bipolar disorder, a condition with alternating episodes of depression and mania
In addition to the disorders listed above, weight loss is common in people with Huntington’s disease, especially as the disease progresses.
The onset and progression of Huntington’s disease in young people may be slightly different from that in adults. Problems that often arise early in the course of the disease include:
Behavioral changes
Difficulty paying attention
Rapid and significant decline in overall academic performance
Tight and stiff muscles affecting gait (especially in young children)
Tremors or slight involuntary movements
Frequent falls or clumsiness
Huntington’s disease is caused by an inherited difference in a single gene. Huntington’s disease is an autosomal dominant disease, which means that a person needs only one copy of the atypical gene to develop the disease.
With the exception of genes on the sex chromosomes, a person inherits two copies of each gene, one copy from each parent. A parent with an abnormal gene could pass on the abnormal copy of the gene or the healthy copy. Therefore, each child in the family has a 50% chance of inheriting the gene that causes the genetic disorder.
After Huntington’s disease begins, a person’s functional abilities gradually deteriorate over time. The rate of progression and duration of the disease varies. The time from first symptoms to death is often around 10-30 years. Juvenile Huntington’s disease usually leads to death within 10 years of symptoms appearing.
Clinical depression associated with Huntington’s disease can increase the risk of suicide. Some research suggests that the greatest risk of suicide occurs before a diagnosis is made and in the middle stages of the disease, when a person begins to lose independence
Eventually, a person with Huntington’s disease needs help with all activities of daily living and with care. Towards the end of the disease, the person will likely be bedridden and unable to speak. Someone with Huntington’s disease is usually able to understand speech and has an awareness of family and friends, although some do not recognize family members.
Common causes of death include:
Pneumonia or other infections
Complications related to the inability to swallow
People with a known family history of Huntington’s disease are understandably concerned about passing the Huntington’s gene to their children. These people may consider genetic testing and family planning options.
If an at-risk parent is considering genetic testing, it may be helpful to meet with a genetic counselor. A genetic counselor will discuss the potential risks of a positive test result, which would indicate that the parent will develop the disease. In addition, couples will have to make further choices about whether to have children or consider alternatives, such as prenatal testing for the gene or in vitro fertilization with donor sperm or egg cells.
Another option for couples is in vitro fertilization and preimplantation genetic diagnosis. In this process, the eggs are taken from the ovaries and fertilized with the father’s sperm in the laboratory. Embryos are tested for the presence of the Huntington’s gene and only those that test negative for the Huntington’s gene are implanted into the mother’s uterus.
In Italy, it is estimated that the disease affects around 6-7,000 people, while individuals currently at risk of getting sick would be 30-40,000.
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