Huntington’s Disease Starts Before Symptoms

A new study headed by researchers at Boston Children’s Hospital and Harvard Medical School reveals how Huntington’s illness begins well before symptoms manifest — and indicates that the process can be inhibited in mice to prevent Huntington’s cognitive impairments.

If the findings hold true in humans, it opens the door of intervening early in the disease in patients who possess the Huntington’s gene mutation.

The study, which was published in Nature Medicine on October 9, may possibly offer insight on other neurodegenerative illnesses.

The researchers discovered in patient tissue samples and mouse models that two immune system players — complement proteins and microglia — are activated extremely early in Huntington’s disease, leading to synaptic loss in the brain before cognitive and motor symptoms appear. The researchers discovered how and where synapses die.

The findings support a potential treatment for the condition that is presently being tested in clinical trials.

Senior author Beth Stevens, an HMS associate professor of neurology at Boston Children’s Hospital, and first author Dan Wilton, an HMS research fellow in neurology in the Stevens lab, led the study.

What exactly is Huntington’s disease?
Huntington’s disease is a genetic ailment that causes brain cells to degrade, resulting in difficulties with mobility, thinking, emotion, behavior, and personality.

Symptoms usually emerge in middle age, however they might appear earlier or later in life. They worsen with time and eventually kill. There is presently no cure and no method to stop the progression of symptoms.

Despite its rarity, Huntington’s disease is the most frequent single-gene neurodegenerative condition, affecting 15,000 to 30,000 persons in the United States at any given time.

The involvement of complement proteins is being investigated

The Stevens team was among the first to demonstrate in 2012 that immune cells in the brain called microglia engulf and prune synapses during normal brain development, fine-tuning the brain’s connections.

The researchers also discovered that complement proteins, another component of the immune system, flag synapses that should be eliminated.

Stevens and colleagues hypothesized that in disorders characterized by synapse loss, such as Alzheimer’s disease and schizophrenia, this pruning mechanism reactivates abnormally.

These disorders, however, are challenging to research since they are caused by several genes and lack adequate animal models.

Huntington’s disease provided an excellent research opportunity.

“Huntington’s disease has one causal gene, huntingtin, and a very selective and stereotyped pathology, allowing us to observe the disease process at very early stages,” said Stevens, a member of Boston Children’s F.M. Kirby Neurobiology Center.

“We were able to investigate whether the complement- and microglia-mediated pruning mechanisms were activated early.” And, if so, are we able to intervene?”

premature pruning

Wilton and colleagues demonstrated, using a mouse model and postmortem brain samples from Huntington’s disease patients, that complement proteins and microglia are activated very early in the illness — before cognitive and motor symptoms appear — and that they target a specific vulnerable brain circuit.

Despite the fact that the mutant huntingtin gene is expressed in every cell, postmortem brain tissue revealed a selective loss of corticostriatal connections in the basal ganglia.

Corticostriatal circuits have been linked to movement and learning which activities result in positive consequences or rewards.

The researchers discovered higher quantities of complement proteins at synapses in these circuits.

The researchers reduced synapse loss in their mouse model by blocking the complement protein C1q using an antibody or by genetically eliminating the complement receptor CR3 on microglia.

They also protected cognitive impairments in mice, particularly those related to visual discrimination learning and cognitive flexibility.

“Some cognitive deficits tend to develop much earlier than motor defects in Huntington’s disease,” says Wilton. “There is evidence that this occurs in humans, too.”

“Our mouse model does develop some slight motor defects that are also resolved with complement-blocking strategies,” he went on to say.

Potential early biomarker

The study supports an antibody-based therapy for Huntington’s disease that targets C1q.

“Dan, for the first time, showed a specific mechanism for corticostriatal synaptic elimination, demonstrating the selective vulnerability of this synaptic connection and providing insight into what is happening at the earliest stages of the disease,” Stevens said in a statement.

Another hopeful clinical finding: complement protein levels were raised in the cerebral fluid of Huntington’s disease patients even before they displayed motor symptoms.

“We’re excited by the idea that we could identify neuroimmune biomarkers that could stratify people at the earliest stage and prioritize some for treatment,” Stevens was quoted as saying. “If you had clinical samples such as cerebrospinal fluid, measuring these biomarkers could bring insight into what is happening in the brain.”

Stevens believes that comparable mechanisms and biomarkers may apply to other neurodegenerative conditions being studied in her group, such as Alzheimer’s and frontotemporal dementia.

But, for the time being, she and Wilton seek to figure out how the huntingtin mutation causes complement activation in the first place.

They understand that the mutant gene must be expressed precisely in cortical and striatal neurons in order to activate the synaptic elimination mechanism. However, how the corticostriatal inputs are preferentially targeted remains unknown.

“Huntington’s is a really nice model to tease this out,” Stevens went on to say. “That’s a major future direction for our group.”

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