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How skin cells-turned-neurons are shedding light on Huntington’s disease

Researchers at Washington University School of Medicine have discovered the mechanism driving cognitive decline in Huntington’s disease patients. The study, published in Nature Neuroscience, also points to how certain treatments could be used to intervene in this process and prevent neurodegeneration.

Adults only

Huntington’s is a fatal neurodegenerative condition caused by a defective gene that is often passed from parent to offspring. Some of the most common symptoms include involuntary movements, muscle rigidity, slow or unusual eye movements, and difficulty swallowing. Symptoms typically only begin in adulthood, and most patients survive for a maximum of 20 years after onset.

The disease targets brain cells known as medium spiny neurons, and it is the loss of these cells that causes involuntary muscle movements, impaired mental health and cognitive decline. Despite being relatively well studied, it is still not clear how the aging process triggers the loss of these neurons and the onset of symptoms in patients. In a bid to understand the disease better (and to see if there are ways to delay or prevent neurodegeneration) Andrew Yoo and his team from Washington University School of Medicine turned to a special type of skin cell – fibroblasts.  

Skin deep

The team took skin samples from Huntington’s disease (HD) patients and reprogrammed them to form medium spiny neurons – by exposing them to different signalling molecules. “We collected skin cell samples from different patients at a range of ages and modelled the disease before and after symptoms developed, which allowed us to identify the differences between younger and older patients with Huntington’s disease,” Yoo said. Traditionally, stem cells are used in these types of studies, but this creates cells in an early developmental state – not very useful when you’re trying to understand how Huntington’s affects older adults.

“We knew there must be some change that takes place as patients age. They all have a genetic mutation in the Huntingtin gene. We wanted to find the difference between young patients who have no symptoms and older patients who actively show signs of the disease,” added Yoo.

Autophagy and aging

They found that there were clear differences in chromatin accessibility between those cells from older HD patients and those from younger pre-HD patients. On further analysis, they saw that these medium spiny neurons produced higher levels of a microRNA (miRNA) molecule called miR-29b-3p. This finding was not seen in younger Huntington’s patients, nor in healthy individuals of any age.

It appears that as HD patients age, they produce more miRNA. This sets off a chain of events that impairs the process of autophagy in the cells – the body’s cellular recycling system. If cells are inhibited from undergoing autophagy, they instead accumulate and eventually die. Because this process occurs across many cells, any treatment to target it has many other potential applications.

“Our study reveals how aging triggers a loss of the crucial process of autophagy – and hints at how we might try to restore this important function, with the aim of delaying or even preventing Huntington’s disease,” said Yoo.

Hunting for a cure

Now they knew what was happening, the researchers turned their attention to finding a potential way to treat this. They showed that reducing the levels of miRNA in the cells allowed autophagy to continue and protected the neurons from death. They were also able to augment autophagy by adding a chemical compound, G2, into the mix. This molecule was found by screening for potential autophagy enhancer drugs. As the levels of G2 increased, so too did the neuron protection from cell death.

Alongside a possible treatment for Huntington’s, the team also uncovered a clue about the normal aging process. It seems that, in comparison to healthy young adults, levels of miRNA are also elevated in healthy older adults. The authors suggest this might point to one mechanism through which aging impacts cognitive functioning.

“By modelling different stages of the disease across the life span, we can identify how aging plays a role in disease onset,” Yoo said. “With that information, we can begin to look for ways to delay that onset. Our study also suggests that the triggering molecule for the onset of Huntington’s disease may play some role in age-associated decline in neuronal function generally. Understanding the component of aging that sets off neurodegeneration may help in developing new strategies for treatment and prevention of Huntington’s disease and other neurodegenerative conditions that develop at older ages.”