A microglia cell (shown in green) and corticostriatal synapses (purple) from a patient with Huntington’s disease. Image: Dan Wilton
At a glance:
- Work in patient tissue samples and mouse models reveals that two players in the immune system — complement proteins and microglia — lead to synapse loss in the brain before cognitive and motor symptoms emerge.
- Blocking a specific complement protein prevented cognitive problems in mice.
- Findings raise the possibility of intervening early in the disease in people with the Huntington’s gene mutation.
A new study led by researchers at Boston Children’s Hospital and Harvard Medical School reveals how the process of Huntington’s disease begins well before symptoms appear — and shows that in mice, the process can be blocked to prevent cognitive problems related to Huntington’s.
If the findings hold true in humans, they raise the possibility of intervening early in the disease in people who carry the Huntington’s gene mutation.
The work, published Oct. 9 in Nature Medicine, also could shed light on other neurodegenerative disorders.
The team found in patient tissue samples and mouse models that two players in the immune system — complement proteins and microglia — are activated very early in Huntington’s, leading to loss of synapses in the brain before cognitive and motor symptoms emerge. The researchers revealed how and where the synapses are lost.
The findings corroborate a potential treatment that’s currently in clinical trials for the disease.
The study was led by senior author Beth Stevens, HMS associate professor of neurology at Boston Children’s, and first author Dan Wilton, HMS research fellow in neurology in the Stevens lab.
What is Huntington’s disease?
Huntington’s disease is an inherited disorder that causes brain cells to break down, typically resulting in problems with movement, thinking, emotion, behavior, and personality.
Symptoms most often appear in middle age but can start earlier or later in life. They worsen over time and are ultimately fatal. There is currently no cure and no way to stop symptoms from progressing.
Though rare, Huntington’s is the most common single-gene neurodegenerative disorder, affecting an estimated 15,000 to 30,000 people in the U.S. at any given time.
Investigating the role of complement proteins
In 2012, the Stevens lab was among the first to show that immune cells in the brain known as microglia engulf and prune synapses during normal brain development, fine-tuning the brain’s connections.
The lab also showed that complement proteins, another part of the immune system, tag synapses meant for elimination.
Stevens and team speculated that in diseases involving synapse loss, like Alzheimer’s disease and schizophrenia, this pruning process reactivates abnormally.
However, these conditions are difficult to study: They’re caused by multiple genes and lack good animal models.
Huntington’s disease offered an ideal research opportunity.
“Huntington’s 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 the F.M. Kirby Neurobiology Center at Boston Children’s.
“We were able to ask is the complement- and microglia-mediated pruning mechanism activated early. And if so, can we intervene.”
Pruned too soon
Using a mouse model and postmortem brain samples from patients with Huntington’s disease, Wilton and colleagues showed that complement proteins and microglia are activated very early in the illness — before cognitive and motor symptoms emerge — and that they target a specific vulnerable brain circuit.
While the mutant huntingtin gene is expressed in every cell, the postmortem brain tissue showed a selective loss of corticostriatal synapses in the basal ganglia.
Corticostriatal circuits are known to be involved in movement and in learning what actions lead to positive outcomes or reward.
The researchers saw increased levels of complement proteins around the synapses in these circuits.
When the team blocked the complement protein C1q in their mouse model — either with an antibody or by genetically deleting the complement receptor CR3 on microglia — they prevented synapse loss.
They also prevented cognitive defects in the mice, specifically around visual discrimination learning and cognitive flexibility.
“Some cognitive deficits tend to develop much earlier than motor defects in Huntington’s disease,” noted 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 added.
Possible early biomarker
The study validates a treatment already in clinical trials for Huntington’s that blocks C1q with an antibody.
“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.
Another clinically promising finding: levels of complement proteins were elevated in the cerebrospinal fluid of patients with Huntington’s disease even before they developed 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 said. “If you had clinical samples such as cerebrospinal fluid, measuring these biomarkers could bring insight into what is happening in the brain.”
Stevens thinks similar mechanisms and biomarkers may apply to other neurodegenerative disorders such as Alzheimer’s and frontotemporal dementia, which her lab is exploring.
But most immediately, she and Wilton hope to unravel how the huntingtin mutation leads to complement activation to begin with.
They know that expression of the mutant gene must be expressed specifically in cortical and striatal neurons to initiate the synaptic elimination mechanism. But how the corticostriatal inputs are selectively targeted remain to be determined.
“Huntington’s is a really nice model to tease this out,” said Stevens. “That’s a major future direction for our group.”
Authorship, funding, disclosures
Stevens is also affiliated with the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard and with the Howard Hughes Medical Institute.
Additional authors are Kevin Mastro, Molly D. Heller, Frederick W. Gergits, Carly Rose Willing, Jacyln B. Fahey, Arnaud Frouin, Anthony Daggett, Xiaofeng Gu, Yejin A. Kim, Richard L. M. Faull, Suman Jayadev, Ted Yednock, and X. William Yang.
This study was supported by the National Institutes of Health (R01NS084298, P30-HD-18655, U54HD090255) and the CHDI Foundation (project record A-9181). Wilton has been supported by an HD Human Biology fellowship from the Huntington’s Disease Society of America.
Stevens serves on the scientific advisory board of Annexon Biosciences and is a minor shareholder of this company. Yednock is the chief innovation officer of Annexon Biosciences, a publicly traded biotechnology company.
